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EP1146044B1 - CNS active cyclobuta-indole carboxamide derivatives, processes for their preparation and pharmaceutical compositions containing them - Google Patents

CNS active cyclobuta-indole carboxamide derivatives, processes for their preparation and pharmaceutical compositions containing them Download PDF

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Publication number
EP1146044B1
EP1146044B1 EP01400939A EP01400939A EP1146044B1 EP 1146044 B1 EP1146044 B1 EP 1146044B1 EP 01400939 A EP01400939 A EP 01400939A EP 01400939 A EP01400939 A EP 01400939A EP 1146044 B1 EP1146044 B1 EP 1146044B1
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formula
compounds
group
branched
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German (de)
French (fr)
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EP1146044A1 (en
Inventor
Jean-Louis Peglion
Bertrand Goument
Mark Millan
Françoise Lejeune
Didier Cussac
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel cyclobuta-indole carboxamide derivatives, their preparation process and the pharmaceutical compositions containing them.
  • the compounds of the present invention are useful in the treatment of central nervous system such as anxiety, panic attacks, obsessive-compulsive, phobias, impulsive disorders, drug abuse, disorders of cognition, psychoses, depressions and mood disorders.
  • the compounds of the present invention in addition to being novel, have been found to be very active for the treatment of diseases of the central nervous system, and more particularly demonstrated strong activity in the Vogel conflict test in the rat, and in the mouse burrow test.
  • the obtained results in the first test make it possible to propose the use of the compounds of the invention in the treatment of clinical phenomena related to anxiety, and those obtained in the second test demonstrate the strong therapeutic potential of the compounds of the invention in the treatment diseases related to mood disorders.
  • aryl group there is understood a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, and benzocyclobutyl, each of these groups being optionally substituted with one or more groups, identical or different, chosen from halogen atoms.
  • heteroaryl group an aromatic monocyclic system or bicyclic, one of which is aromatic, the other being aromatic or partially hydrogenated, 5 to 12 chains, containing one, two or three heteroatoms, identical or different, chosen from oxygen, nitrogen and sulfur, each of these groups being optionally substituted by one or more groups, which are identical or different, selected from the substituents described for the aryl group previously defined.
  • cycloalkyl group we understand a mono- or polycyclic system, from 3 to 12 chains, possibly containing one or more unsaturations, these conferring no aromatic character to said ring system.
  • Isomers include optical isomers (enantiomers and diastereoisomers).
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, camphoric, etc.
  • pharmaceutically acceptable bases mention may be made, without limitation sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.
  • the preferred compounds of the invention are the compounds of formula (I) in which R 2 represents a hydrogen atom.
  • the preferred compounds of the invention are the compounds of formula (I) in which R 2 represents a group of formula in which T is as defined in formula (I), n is 1, and R 1 represents a cyano group or an amino group substituted with one or two groups, which may be identical or different, chosen from linear or branched (C 1 -C 6 ) alkyl and linear or branched (C 1 -C 6 ) arylalkyl.
  • the preferred compounds of the invention are the compounds of formula (I), in which n is 0, R 1 represents a hydrogen atom or a cyano group, and R 2 represents a grouping. of formula -UVW wherein U represents a single bond, V represents a group of formula S (O) p with p as defined in formula (I) and W represents an aryl group.
  • the preferred compounds of the invention are the compounds of formula (I) in which n is 0, R 1 represents a hydrogen atom or a cyano group, and R 2 represents a hydrogen atom. 'hydrogen.
  • the preferred substituent R 3 according to the invention is the heteroaryl group, and more particularly the pyridinyl group.
  • the invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material: in which R ' 1 represents a group chosen from hydrogen atom, cyano group, hydroxymethylene group, carboxy group and linear or branched (C 1 -C 6 ) alkoxycarbonyl group, compound of formula (II) which is reacted under reductive amination conditions with a compound of formula (III) : (AO) 2 CHCHO (III) in which A represents a linear or branched (C 1 -C 6 ) alkyl group, to give compounds of formula (IV) : in which A and R ' 1 are as defined above, compounds of formula (IV) which are treated with a compound of formula (V) : ClSO 2 E (V) in which E represents a linear or branched (C 1 -C 4 ) alkyl group, phenyl or p-toluyl, to yield compounds of formula (VI) :
  • the compounds of formula (II), (III), (V), (X), (XI), (XV), (XVIII) and (XXI) are either known products, ie products obtained from substances known to classical processes of organic chemistry.
  • the compounds of the present invention are useful as a drug in the treatment of anxiety, panic attacks, obsessive-compulsive disorder, phobias, impulsive disorders, drug abuse, disorders of cognition, psychoses, depressions, and mood disorders.
  • the subject of the present invention is also the pharmaceutical compositions containing as active ingredient at least one compound of formula (I), its optical isomers, its salts addition to a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic excipients or carriers, pharmaceutically acceptable.
  • compositions according to the invention are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per or transcutaneous, nasal, rectal, perlingual, ocular or respiratory, and especially simple or sugar-coated tablets, tablets sublinguals, capsules, capsules, suppositories, creams, ointments, gels dermal, injectable or drinkable preparations, aerosols, eye drops or nasal, etc.
  • the dosage varies depending on the age and weight of the patient, the route of administration, the nature of and the severity of the condition, and the intake of any associated treatments and ranges from 0.5 mg to 25 mg in one or more doses per day.
  • the melting points were determined either on the Kofler heating stage (K.) or on the hot stage under microscope (M.K.). When the compound exists in salt form, the melting point given corresponds to that of the salified product.
  • Step 1 5 - [(2,2-Dimethoxyethyl) amino] benzocyclobutane-1-carbonitrile
  • a suspension of 13.5 g of 5-amino-benzocyclobutane-1-carbonitrile in 400 ml of 1,2-dichloroethane is added dropwise, 26.5 ml of a solution of 2,2-dimethoxy. 45% acetaldehyde in tert-butyl methyl ether, followed by 16 ml of acetic acid and then, by fraction, 39.7 g of sodium triacetoxyborohydride.
  • the reaction medium is brought to room temperature, stirred for 1 h 15 and then hydrolyzed by pouring the medium into 500 ml of an aqueous solution saturated with NaHCO 3 .
  • the organic phase is separated, washed with water, and concentrated under reduced pressure to yield the desired product.
  • Step 2 5- [N- (2,2-Dimethoxyethyl) -N- (methylsulfonyl) amino] benzocyclobutane-1-carbonitrile
  • Step 3 1- (Methylsulfonyl) -5,6-dihydro-1H-cyclobuta [f] indole-6-carbonitrile
  • the product is obtained according to the process of Stage 4 of Preparation 1 using as substrate the regioisomer obtained in Step 3 of Preparation 1.
  • the product is obtained from the compound obtained in stage 1, according to the method of stage 5 of preparation 1.
  • Step 1 4 - [(2,2-Dimethoxyethyl) amino] benzocyclobutane
  • the product is obtained from the compound of the previous stage, according to the method of stage 1 of preparation 1.
  • Step 3 Methyl 5- [N- (2,2-dimethoxyethyl) -N- (methylsulfonyl) amino] -1-benzocyclobutanecarboxylate
  • the product is obtained from the compound of the previous stage, according to the method of stage 2 of preparation 1.
  • Step 4 Methyl 1- (methylsulfonyl) -5,6-dihydro-1H-cyclobuta [f] indole-6-carboxylate
  • the product is obtained from the compound of the previous stage, according to the method of stage 3 of preparation 1.
  • Step 5 [1- (Methylsulfonyl) -5,6-dihydro-1H-cyclobuta [f] indol-6-yl] methanol
  • the product is obtained from the compound of the previous stage, according to the process of stage 4 of preparation 1.
  • Step 7 2,3,5,6-Tetrahydro-1H-cyclobuta [f] indol-6-ylmethanol
  • the product is obtained from the compound of the preceding stage, according to the process of stage 5 of the preparation 1.
  • the compound is isolated after silica gel chromatography (dichloromethane / ethanol: 97/3).
  • Step 3 N- (1-Cyanobenzocyclobutan-6-yl) acetamide
  • a stream of gaseous HCl is introduced until saturation of a solution of 5.04 g of product obtained in Step 3 in 400 ml of anhydrous ethanol at 0 ° C.
  • the reaction medium is then refluxed for 18 hours.
  • concentration of the solvent the residue is taken up in iced water, basified with sodium carbonate solution and extracted with dichlorométane.
  • the organic phase is separated, dried and concentrated to obtain the expected product.
  • the product is obtained from the compound of the previous stage according to the processes of the stages 2 to 7 of preparation 4.
  • the product is obtained according to the process of Preparation 1, Steps 1 to 5, using as substrate in Step 1 4-amino-1-benzocyclobutanecarbonitrile. Melting point : 103-107 ° C
  • Step 1 6 - [(2-Methyl-3-pyridinyl) oxy] -3-pyridinylamine
  • the product is obtained according to the method of Example 1, using as substrate the compound of Preparation 4. Melting point : 195-200 ° C (MK)
  • the product is obtained according to the method of Example 1, using as substrate the compound of Preparation 1. Melting point : 203-207 ° C (MK)
  • the product is obtained according to the method of Example 1, using as substrate the compound of Preparation 6. Melting point : 209-211 ° C (MK)
  • the product is obtained according to the method of Example 1, using as substrate the compound of Preparation 7. Melting point : 167-173 ° C (MK)
  • the product is obtained according to the method of Example 1, using as substrate the compound of Preparation 2. Melting point : 203-205 ° C (MK)
  • the product is obtained according to the method of Example 1, using as substrate the compound of Preparation 5. Melting point : 216-220 ° C (MK)
  • Step 1 6- (1-Hydroxycyclohexyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-6-carbonitrile
  • Step 2 6- (1-Hydroxycyclohexyl) -1- (methylsulfonyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-6-carbonitrile
  • Step 3 1- [6- (Aminomethyl) -1- (methylsulfonyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indol-6-yl] cyclohexanol
  • Step 4 1- [6 - [(Dimethylamino) methyl] -1- (methylsulfonyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indol-6-yl] cyclohexanol
  • Step 5 1- ⁇ 6 - [(Dimethylamino) methyl] -2,3,5,6-tetrahydro-1H-cyclobuta [f] indol-6-yl ⁇ cyclohexanol
  • Step 6 6 - [(Dimethylamino) methyl] -6- (1-hydroxycyclohexyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide
  • the product is obtained according to the method of Example 1, using as substrate the product obtained in Step 5. Melting point : 207-209 ° C
  • Step 1 6- (Phenylsulfanyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole 6-carbonitrile
  • Step 2 6-Cyano-6- (phenylsulfanyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide
  • Step 1 6-cyclohexyl-2,3,5,6-tetrahydro-1H-cyclobuta [f] indole 6-carbonitrile
  • Step 2 6-Cyano-6-cyclohexyl-N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide
  • Step 1 6-Cyclohexyl-2,3,5,6-tetrahydro-1H-cyclobuta [f] indole
  • a solution of 0.5 g of product obtained in Step 1 of Example 10 in 10 ml of anhydrous tetrahydrofuran and 0.11 ml of absolute ethanol are poured onto 20 ml of ammonia liquid at a temperature of -78 ° C, then 0.15 g of sodium are introduced in portions. After 30 minutes of contact at this temperature, the reaction medium is treated with 0.83 g of ammonium chloride. After evaporation of the ammonia, the residue is taken up by a saturated solution of ammonium chloride, extracted with ether and the ethereal phases are washed, dried and concentrated to yield the expected product.
  • Step 2 6-Cyclohexyl-N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide
  • a mixture consisting of 0.5 g of the product obtained in Stage 1 of Example 9, 0.6 g of the product of Preparation 9, 0.16 ml of triethylamine and 16 ml of dimethylformamide is heated at 100 ° C. for 1 hour. hour. After evaporation of the dimethylformamide, the residue is taken up in 100 ml of dichloromethane, washed with 10% sodium hydroxide, with water, then dried and concentrated under reduced pressure, to conduct after purification on silica (dichloromethane / ethanol / NH 4 OH / 98/2 / 0.4) and recrystallization of acetonitrile, to the expected product
  • the test is carried out on Wistar male rats (IFFA-CREDO) weighing 230-250 g, housed in pet shops in groups of 4 on sawdust, in cages with drink and food at will for 5 days before their use and submitted to the following conditions: temperature (21 ⁇ 1 ° C), humidity (60 ⁇ 5%) and daytime cycle of 12 hours (7:00 to 19:00 h).
  • temperature 21 ⁇ 1 ° C
  • humidity 60 ⁇ 5%
  • daytime cycle of 12 hours 7:00 to 19:00 h.
  • the animals are transferred to the experimental room where they will stay until Friday, the day of Test.
  • the animals For 4 days, from Monday to Thursday, the animals have only one hour per day of access to the drink (from 9:00 to 10:00).
  • the day before the test from 15:00 pm, the animals are isolated in grid cages, without drink or food.
  • the test takes place in a transparent plastic cage located in a soundproof and ventilated enclosure.
  • the cage has a chromed steel floor.
  • the metal tip of the bottle containing the drink enters the cage at a height of 6 cm above the metal floor.
  • the floor and the tip of the bottle are connected by electrical cables to a device that records the licking of the animal and controls the administration of electric shocks.
  • the apparatus is set so that the animal receives an electric shock (between tip and metal floor) every 20 lobes of the tip.
  • the animal receives an injection (sc) of physiological saline (control) or product to be tested, 30 minutes before being placed in the test cage.
  • MED minimum effective dose
  • This dose is 2.5 mg / kg, sc for the product of Example 1.
  • Product results from Example 1 Doses mg / kg, sc Licks punished (1 shock / 20 licks) NOT 0 142.7 ⁇ 31.9 10 0.63 197.5 ⁇ 59.5 8 2.5 560.1 ⁇ 67.0 8 10.0 499.3 ⁇ 95.3 7
  • mice of NMRI strain Male mice of NMRI strain (Iffa-Credo, L'Arbresle, France), weighing 20-25 g on the day of the experiment, are placed individually in Macrolon boxes (30 x 18 x 19 cm) containing 5 cm of sawdust and covered by a perforated plexiglass plate. Twenty-four glass balls "cat's eye” are regularly distributed on the sawdust on the periphery of the box. After 30 minutes of free exploration, the animals are removed from the box and the number of buried logs is counted.
  • the MED (minimum effective dose) for the product of Example 1 is 2.5 mg / kg sc

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Description

La présente invention concerne de nouveaux dérivés de cyclobuta-indole carboxamide, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent.The present invention relates to novel cyclobuta-indole carboxamide derivatives, their preparation process and the pharmaceutical compositions containing them.

Les composés de la présente invention sont utiles dans le traitement des maladies du système nerveux central telles que l'anxiété, les attaques de panique, les troubles obsessionnels compulsifs, les phobies, les troubles impulsifs, l'abus de drogue, les troubles de la cognition, les psychoses, les dépressions et les troubles de l'humeur.The compounds of the present invention are useful in the treatment of central nervous system such as anxiety, panic attacks, obsessive-compulsive, phobias, impulsive disorders, drug abuse, disorders of cognition, psychoses, depressions and mood disorders.

De nombreux dérivés polycycliques et hétérocycliques contenant une fonction urée ont été décrits dans la littérature comme étant des antagonistes de divers récepteurs sérotoninergiques, leur conférant ainsi une utilité pour le traitement des maladies du système nerveux central. C'est le cas plus particulièrement des demandes de brevets WO 95/29177, WO 96/23783 et WO 98/47868. Le brevet US 5,514,690 décrit, quant à lui, des dérivés d'aminocarbonylquinoline ou indoline et les revendique pour leur propriété d'activation des pompes à potassium.Many polycyclic and heterocyclic derivatives containing a urea function have been described in the literature as antagonists of various receptors serotonin, thus conferring on them a useful role in the treatment of central nervous system. This is particularly the case for patent applications WO 95/29177, WO 96/23783 and WO 98/47868. US Patent 5,514,690 describes, meanwhile, derivatives of aminocarbonylquinoline or indoline and claims them for their property activation of potassium pumps.

Les composés de la présente invention, outre le fait qu'ils soient nouveaux, se sont révélés très actifs pour le traitement des maladies du système nerveux central, et plus particulièrement ont démontrés une forte activité dans le test de conflit de Vogel chez le rat, ainsi que dans le test d'enfouissement de billes chez la souris. Les résultats obtenus dans le premier test permettent de proposer l'utilisation des composés de l'invention dans le traitement des phénomènes cliniques liés à l'anxiété, et ceux obtenus dans le second test démontrent le fort potentiel thérapeutique des composés de l'invention dans le traitement des maladies liées aux troubles de l'humeur.The compounds of the present invention, in addition to being novel, have been found to be very active for the treatment of diseases of the central nervous system, and more particularly demonstrated strong activity in the Vogel conflict test in the rat, and in the mouse burrow test. The obtained results in the first test make it possible to propose the use of the compounds of the invention in the treatment of clinical phenomena related to anxiety, and those obtained in the second test demonstrate the strong therapeutic potential of the compounds of the invention in the treatment diseases related to mood disorders.

Plus particulièrement, la présente invention concerne les composés de formule (I) :

Figure 00010001
dans laquelle :

  • n représente un entier compris entre 0 et 6,
  • R1 représente un groupement choisi parmi hydrogène, hydroxy, cyano, alkoxy (C1-C6) linéaire ou ramifié, alkoxycarbonyle (C1-C6) linéaire ou ramifié, carboxy, aminocarbonyle (la partie amino étant éventuellement substituée par un ou deux groupements, identiques ou différents, choisis parmi alkyle (C1-C6) linéaire ou ramifié, aryle et arylalkyle (C1-C6) linéaire ou ramifié), et NR4R5 dans lequel R4 et R5, identiques ou différents, représentent un groupement choisi parmi alkyle (C1-C6) linéaire ou ramifié, aryle, arylalkyle (C1-C6) linéaire ou ramifié, hétéroaryle, hétéroarylalkyle (C1-C6) linéaire ou ramifié, cycloalkyle, cycloalkylalkyle (C1-C6) linéaire ou ramifié, alkényle (C2-C6) linéaire ou ramifié, et alkynyle (C2-C6) linéaire ou ramifié,
  • R2 représente un groupement choisi parmi atome d'hydrogène, groupement alkyle (C1-C6) linéaire ou ramifié, hydroxyméthyle, groupement de formule
    Figure 00020001
    et -U-V-W
    dans lesquels :
    • T représente un groupement cycloalkyle (C3-C12) monocyclique ou polycyclique, dont l'un des atomes de carbone du cycloalkyle peut éventuellement être remplacé par un groupement choisi parmi atome d'oxygène, atome de sélénium, groupement de formule S(O)p dans laquelle p représente un entier compris entre 0 et 2 inclus, et groupement de formule SiR6R7 dans laquelle R6 et R7, identiques ou différents, représentent un groupement alkyle (C1-C6) linéaire ou ramifié,
    • U représente une liaison ou un groupement méthylène,
    • V représente une liaison, un atome d'oxygène ou un groupement S(O)q dans lequel q est un entier compris entre 0 et 2 inclus,
    • W représente un groupement choisi parmi aryle, arylalkyle (C1-C6) linéaire ou ramifié, cycloalkyle, et cycloalkylalkyle (C1-C6) linéaire ou ramifié,
  • R3 représente un groupement choisi parmi atome d'hydrogène, groupement alkyle (C1-C6) linéaire ou ramifié, aryle, et hétéroaryle,
    • leurs isomères ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable. More particularly, the present invention relates to the compounds of formula (I):
    Figure 00010001
    in which :
  • n represents an integer between 0 and 6,
  • R 1 represents a group selected from hydrogen, hydroxy, cyano, alkoxy (C 1 -C 6) linear or branched alkoxycarbonyl (C 1 -C 6) linear or branched, carboxy, aminocarbonyl (the amino moiety being optionally substituted by one or two groups, which are identical or different, chosen from linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) aryl and arylalkyl, and NR 4 R 5 in which R 4 and R 5 , which are identical, or different, represent a group selected from alkyl (C 1 -C 6) linear or branched, aryl, aryl (C 1 -C 6) linear or branched, heteroaryl, heteroaryl (C 1 -C 6) linear or branched, cycloalkyl, cycloalkylalkyl (C 1 -C 6) linear or branched, alkenyl (C 2 -C 6) -straight or branched alkynyl and (C 2 -C 6) -straight or branched
  • R 2 represents a group chosen from hydrogen atom, linear or branched (C 1 -C 6 ) alkyl group, hydroxymethyl, group of formula
    Figure 00020001
    and -UVW
    wherein :
    • T represents a monocyclic or polycyclic cycloalkyl (C 3 -C 12 ) group, one of the carbon atoms of the cycloalkyl may optionally be replaced by a group selected from oxygen atom, selenium atom, group of formula S (O ) p wherein p represents an integer between 0 and 2 inclusive, and group of the formula SiR 6 R 7 wherein R 6 and R 7, identical or different, represent an alkyl group (C 1 -C 6) linear or branched,
    • U represents a bond or a methylene group,
    • V represents a bond, an oxygen atom or a group S (O) q in which q is an integer between 0 and 2 inclusive,
    • W represents a group chosen from linear or branched linear or branched aryl, (C 1 -C 6 ) arylalkyl, cycloalkyl and (C 1 -C 6 ) cycloalkylalkyl,
  • R 3 represents a group chosen from hydrogen atom, linear or branched (C 1 -C 6 ) alkyl group, aryl, and heteroaryl,
    • their isomers as well as their addition salts with a pharmaceutically acceptable acid or base.

    Par groupement aryle, on comprend un groupement choisi parmi phényle, biphényle, naphtyle, dihydronaphtyle, tétrahydronaphtyle, indanyle, indényle, et benzocyclobutyle, chacun de ces groupements étant éventuellement substitué par un ou plusieurs groupements, identiques ou différents, choisis parmi atomes d'halogène, groupements alkyle (C1-C6) linéaire ou ramifié, hydroxy, alkoxy (C1-C6) linéaire ou ramifié, nitro, cyano, trihalogénoalkyle (C1-C6) linéaire ou ramifié, amino, monoalkylamino, dialkylamino (C1-C6) linéaire ou ramifié, trihalogénoalkoxy (C1-C6) linéaire ou ramifié, aminoalkyl(C1-C6)aminocarbonyle (les atomes d'azote de chacune des parties amino étant éventuellement substitués par des groupements alkyle (C1-C6) linéaires ou ramifiés, identiques ou différents), pyridinyle, pyridinyloxy, pyridinyloxyméthyle, ces trois derniers groupements étant éventuellement substitués par un groupement alkyle (C1-C6) linéaire ou ramifié.By aryl group, there is understood a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, and benzocyclobutyl, each of these groups being optionally substituted with one or more groups, identical or different, chosen from halogen atoms. , alkyl (C 1 -C 6) linear or branched, hydroxy, alkoxy (C 1 -C 6) linear or branched, nitro, cyano, trihalo (C 1 -C 6) linear or branched, amino, monoalkylamino, dialkylamino ( C 1 -C 6 ) linear or branched, trihaloalkoxy (C 1 -C 6 ) linear or branched, aminoalkyl (C 1 -C 6 ) aminocarbonyl (the nitrogen atoms of each of the amino portions being optionally substituted with alkyl groups ( C 1 -C 6 ) linear or branched, identical or different), pyridinyl, pyridinyloxy, pyridinyloxymethyl, these last three groups being optionally substituted with a linear (C 1 -C 6 ) alkyl group or branched.

    Par groupement hétéroaryle, on comprend un système monocyclique aromatique ou bicyclique dont l'un des cycles est aromatique, l'autre cycle étant aromatique ou partiellement hydrogéné, de 5 à 12 chaínons, contenant un, deux ou trois hétéroatomes, identiques ou différents, choisis parmi oxygène, azote et soufre, chacun de ces groupements étant éventuellement substitué par un ou plusieurs groupements, identiques ou différents, choisis parmi les substituants décrits pour le groupement aryle précédemment défini.By heteroaryl group, an aromatic monocyclic system or bicyclic, one of which is aromatic, the other being aromatic or partially hydrogenated, 5 to 12 chains, containing one, two or three heteroatoms, identical or different, chosen from oxygen, nitrogen and sulfur, each of these groups being optionally substituted by one or more groups, which are identical or different, selected from the substituents described for the aryl group previously defined.

    Par groupement cycloalkyle, on comprend un système mono- ou polycyclique, de 3 à 12 chaínons, contenant éventuellement une ou plusieurs insaturations, celles-ci ne conférant pas de caractère aromatique audit système cyclique.By cycloalkyl group, we understand a mono- or polycyclic system, from 3 to 12 chains, possibly containing one or more unsaturations, these conferring no aromatic character to said ring system.

    Par isomères, on comprend les isomères optiques (énantiomères et diastéréoisomères).Isomers include optical isomers (enantiomers and diastereoisomers).

    Parmi les acides pharmaceutiquement acceptables, on peut citer à titre non limitatif les acides chlorhydrique, bromhydrique, sulfurique, phosphonique, acétique, trifluoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, tartrique, maléïque, citrique, ascorbique, oxalique, méthane sulfonique, camphorique, etc...Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, camphoric, etc.

    Parmi les bases pharmaceutiquement acceptables, on peut citer à titre non limitatif l'hydroxyde de sodium, l'hydroxyde de potassium, la triéthylamine, la tertbutylamine, etc...Among the pharmaceutically acceptable bases, mention may be made, without limitation sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

    Selon une variante avantageuse de l'invention, les composés préférés de l'invention sont les composés de formule (I) dans laquelle R2 représente un atome d'hydrogène.According to an advantageous variant of the invention, the preferred compounds of the invention are the compounds of formula (I) in which R 2 represents a hydrogen atom.

    Selon une autre variante avantageuse de l'invention, les composés préférés de l'invention sont les composés de formule (I) dans laquelle R2 représente un groupement de formule

    Figure 00040001
    dans laquelle T est tel que défini dans la formule (I), n est égal à 1,
    et R1 représente un groupement cyano ou un groupement amino substitué par un ou deux groupements, identiques ou différents, choisis parmi alkyle (C1-C6) linéaire ou ramifié, et arylalkyle (C1-C6) linéaire ou ramifié.According to another advantageous variant of the invention, the preferred compounds of the invention are the compounds of formula (I) in which R 2 represents a group of formula
    Figure 00040001
    in which T is as defined in formula (I), n is 1,
    and R 1 represents a cyano group or an amino group substituted with one or two groups, which may be identical or different, chosen from linear or branched (C 1 -C 6 ) alkyl and linear or branched (C 1 -C 6 ) arylalkyl.

    D'une autre façon avantageuse, les composés préférés de l'invention sont les composés de formule (I), dans laquelle n est égal à 0, R1 représente un atome d'hydrogène ou un groupement cyano, et R2 représente un groupement de formule -U-V-W dans laquelle U représente une liaison simple, V représente un groupement de formule S(O)p avec p tel que défini dans la formule (I) et W représente un groupement aryle.In another advantageous manner, the preferred compounds of the invention are the compounds of formula (I), in which n is 0, R 1 represents a hydrogen atom or a cyano group, and R 2 represents a grouping. of formula -UVW wherein U represents a single bond, V represents a group of formula S (O) p with p as defined in formula (I) and W represents an aryl group.

    D'une façon particulièrement avantageuse, les composés préférés de l'invention sont les composés de formule (I) dans laquelle n est égal à 0, R1 représente un atome d'hydrogène ou un groupement cyano, et R2 représente un atome d'hydrogène.In a particularly advantageous manner, the preferred compounds of the invention are the compounds of formula (I) in which n is 0, R 1 represents a hydrogen atom or a cyano group, and R 2 represents a hydrogen atom. 'hydrogen.

    Le substituant R3 préféré selon l'invention est le groupement hétéroaryle, et plus particulièrement le groupement pyridinyle.The preferred substituent R 3 according to the invention is the heteroaryl group, and more particularly the pyridinyl group.

    Les composés préférés de l'invention sont le :

    • N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 5-cyano-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 6-cyano-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 6-(hydroxyméthyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 5-(hydroxyméthyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 7-cyano-N-(3-pyridinyl)-1,2,6,7-tétrahydro-3H-cyclobuta[e]indole-3-carboxamide,
    • 7-(hydroxyméthyl)-N-(3-pyridinyl)-2,3,6,7-tétrahydro-1H-cyclobuta[g]indole-1-carboxamide,
    • 6-[(diméthylamino)méthyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 6-cyano-6-(phénylsulfanyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 6-cyano-6-cyclohéxyl-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 6-cyclohéxyl-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide,
    • 6-cyano-N-{6-[(2-méthyl-3-pyridinyl)oxy]-3-pyridinyl}-6-(phénylsulfanyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide.
    The preferred compounds of the invention are:
    • N - (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide,
    • 5-cyano-N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide,
    • 6-cyano-N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide,
    • 6- (hydroxymethyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide,
    • 5- (hydroxymethyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide,
    • 7-cyano-N- (3-pyridinyl) -1,2,6,7-tetrahydro-3 H -cyclobuta [e] indole-3-carboxamide,
    • 7- (hydroxymethyl) -N- (3-pyridinyl) -2,3,6,7-tetrahydro- 1H- cyclobuta [ g ] indole-1-carboxamide,
    • 6 - [(dimethylamino) methyl] -6- (1-hydroxycyclohexyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide,
    • 6-cyano-6- (phenylsulfanyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [f] indole-1-carboxamide,
    • 6-cyano-6-cyclohexyl-N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [f] indole-1-carboxamide,
    • 6-Cyclohexyl-N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [f] indole-1-carboxamide,
    • 6-cyano-N- {6 - [(2-methyl-3-pyridinyl) oxy] -3-pyridinyl} -6- (phenylsulfanyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [f] indole-1-carboxamide.

    Les isomères ainsi que les sels d'addition à un acide ou à une base pharmaceutiquement acceptable des composés préférés font partie intégrante de l'invention.Isomers as well as addition salts with an acid or a pharmaceutically acceptable base Preferred compounds are an integral part of the invention.

    L'invention concerne aussi le procédé de préparation des composés de formule (I) caractérisé en ce qu'on utilise comme produit de départ un composé de formule (II) :

    Figure 00050001
    dans laquelle R'1 représente un groupement choisi parmi atome d'hydrogène, groupement cyano, hydroxyméthylène, carboxy, et alkoxycarbonyle (C1-C6) linéaire ou ramifié,
    composé de formule (II) qui est mis à réagir dans des conditions d'amination réductrice avec un composé de formule (III) : (AO)2CHCHO   (III) dans laquelle A représente un groupement alkyle (C1-C6) linéaire ou ramifié, pour conduire aux composés de formule (IV) :
    Figure 00060001
    dans laquelle A et R'1 sont tels que définis précédemment,
    composés de formule (IV) qui sont traités par un composé de formule (V) : ClSO2E   (V) dans laquelle E représente un groupement alkyle (C1-C4) linéaire ou ramifié, phényle ou p-toluyle, pour conduire aux composés de formule (VI) :
    Figure 00060002
    dans laquelle A, E et R'1 sont tels que définis précédemment,
    composés de formule (VI) qui sont cyclisés dans des conditions acides, pour conduire aux composés de formule (VII) :
    Figure 00060003
    dans laquelle E et R'1 sont tels que définis précédemment,
    composés de formule (VII) qui sont traités soit par un hydroxyde de métal alcalin dans un solvant alcoolique, soit par le sodium dans l'ammoniaque liquide pour conduire aux composés de formule (VIII) :
    Figure 00060004
    dans laquelle R'1 est tel que défini précédemment,
    composés de formule (VIII) qui sont ensuite réduits selon des conditions classiques de la synthèse organique, pour conduire aux composés de formule (IX) :
    Figure 00070001
    dans laquelle R'1 est tel que défini précédemment,
    composés de formule (IX) qui sont traités par un isocyanate de formule (X) : R3-N=C=O   (X) dans laquelle R3 est tel que défini dans la formule (I),
    pour conduire aux composés de formule (I/a), cas particulier des composés de formule (I) :
    Figure 00070002
    dans laquelle R'1 et R3 sont tels que définis précédemment,
    ou composés de formule (IX), dans le cas particulier où R'1 représente un groupement cyano, que l'on traite :
    * soit par une cétone de formule (XI) :
    Figure 00070003
    dans laquelle T a les mêmes significations que dans la formule (I), pour conduire aux composés de formule (XII) :
    Figure 00070004
    dans laquelle T est tel que défini précédemment,
    composés de formule (XII) qui sont ensuite :
       
    Figure 00070005
    soit traités par un isocyanate de formule (X) telle que décrite précédemment, pour conduire aux composés de formule (I/b), cas particulier des composés de formule (I),
    Figure 00080001
    dans laquelle T et R3 sont tels que définis précédemment,
        soit, après protection de l'amine du groupe indoline, réduits selon les méthodes classiques de la synthèse organique, pour conduire aux composés de formule (XIII) :
    Figure 00080002
    dans laquelle T est tel que défini précédemment et P1 est un groupement protecteur classique,
    composés de formule (XIII) dont la fonction amine primaire est ensuite substituée et transformée en fonction amine secondaire puis tertiaire, en utilisant des méthodes usuelles de la chimie organique, pour conduire aux composés de formule (XIV) :
    Figure 00080003
    dans laquelle R4 et R5 ont les mêmes significations que dans la formule (I) et, T et P1 sont tels que définis précédemment,
    composés de formule (XIV) qui, après déprotection de l'atome d'azote du noyau indoline, sont traités par un composé de formule (X) telle que décrite précédemment, pour conduire aux composés de formule (I/c), cas particulier des composés de formule (I) :
    Figure 00090001
    dans laquelle T, R4, R5 et R3 sont tels que définis précédemment,
    * soit par une base forte ou un alcoolate de métal alcalin, en présence d'un composé de formule (XV) : W1 - X   (XV) dans laquelle W1 représente un groupement alkyle (C1-C6) linéaire ou ramifié, arylalkyle (C1-C6) linéaire ou ramifié, cycloalkyle, ou cycloalkylalkyle (C1-C6) linéaire ou ramifié, et X représente un groupe partant tel qu'un atome d'halogène, un groupement trifluorométhylsulfonate, mésylate ou tosylate,
    pour conduire aux composés de formule (XVI) :
    Figure 00090002
    dans laquelle W1 est tel que défini précédemment,
    composés de formule (XVI) qui sont :
        soit traités par un composé de formule (X) tel que décrit précédemment, pour conduire aux composés de formule (I/d), cas particulier des composés de formule (I) :
    Figure 00090003
    dans laquelle W1 et R3 sont tels que définis précédemment,
        soit transformé, après protection de l'atome d'azote du noyau indoline, comme les composés de formule (XII) en amine primaire, secondaire puis tertiaire, pour conduire après déprotection et traitement en présence d'un composé de formule (X) telle que décrite précédemment, aux composés de formule (I/e), cas particulier des composés de formule (I) :
    Figure 00100001
    dans laquelle W1, R3, R4 et R5 sont tels que définis précédemment,
    * soit par du dibrome dans un solvant organique chloré pour conduire aux composés de formule (XVII) :
    Figure 00100002
    composés de formule (XVII) qui sont mis à réagir avec un composé de formule (XVIII) : W - V1 - H   (XVIII) dans laquelle W a la même signification que dans la formule (I) et V1 représente un atome d'oxygène ou un atome de soufre,
    pour conduire aux composés de formule (XIX) :
    Figure 00100003
    dans laquelle V1 et W sont tels que définis précédemment,
    composés de formule (XIX) qui sont :
        soit traités par un composé de formule (X) tel que décrit précédemment, pour conduire aux composés de formule (I/f), cas particulier des composés de formule (I) :
    Figure 00110001
    dans laquelle R3, V1 et W sont tels que définis précédemment,
    composés de formule (I/f), dans le cas particulier où V1 représente un atome de soufre, qui peuvent être soumis à une oxydation dans des conditions classiques de la synthèse organique, pour conduire aux composés de formule (I/g), cas particulier des composés de formule (I) :
    Figure 00110002
    dans laquelle R3 et W sont tels que définis dans la formule (I) et q1 est un entier compris entre 1 et 2 inclus,
        soit protégés puis transformés, par la même séquence de réactions que les composés de formule (XII), en amine primaire, secondaire et tertiaire, pour conduire après déprotection et traitement par un composé de formule (X), tel que décrit précédemment, aux composés de formule (I/h), cas particulier des composés de formule (I) :
    Figure 00120001
    dans laquelle V1, W, R3, R4 et R5 sont tels que définis précédemment,
    composés de formule (I/h) dans le cas particulier où V1 représente un atome de soufre, qui peuvent être soumis à une oxydation dans des conditions classiques de la synthèse organique, pour conduire aux composés de formule (I/i), cas particulier des composés de formule (I) :
    Figure 00120002
    dans laquelle W, R3, R4, R5 et q1 sont tels que définis précédemment,
    * soit par un hydrure alcalin dans la diméthylformamide en présence de formaldéhyde, pour conduire aux composés de formule (XX) :
    Figure 00120003
    composés de formule (XX) qui sont :
        soit traités par un composé de formule (X) tel que décrit précédemment, pour conduire aux composés de formule (I/j), cas particulier des composés de formule (I) :
    Figure 00130001
    dans laquelle R3 est tel que défini dans la formule (I),
        soit protégés au niveau de l'atome d'azote du noyau indoline, puis traités selon les conditions de la réaction de Mitsunobu par un composé de formule (XXI) : W - OH   (XXI) dans laquelle W est tel que défini dans la formule (I),
    pour conduire, après déprotection de l'atome d'azote du noyau indoline, aux composés de formule (XXII) :
    Figure 00130002
    dans laquelle W est tel que défini précédemment,
    composés de formule (XXII) qui sont :
       ◆ soit traités par un composé de formule (X) tel que décrit précédemment, pour conduire aux composés de formule (I/k), cas particulier des composés de formule (I) :
    Figure 00130003
    dans laquelle R3 et W sont tels que définis précédemment,
       ◆ soit protégés puis transformés, par la même séquence de réaction que les composés de formule (XII), en amine primaire, secondaire et tertiaire, pour conduire après déprotection et traitement par un composé de formule (X), tel que décrit précédemment, aux composés de formule (I/l), cas particulier des composés de formule (I) :
    Figure 00140001
    dans laquelle R3, R4, R5 et W sont tels que définis précédemment,
    les composés (I/a) à (I/l) forment l'ensemble des composés de l'invention, que l'on purifie le cas échéant, selon une technique classique de purification, qui peuvent, si on le désire, être séparés en leurs différents isomères selon une technique classique de séparation, et que l'on transforme, le cas échéant, en leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable.The invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material:
    Figure 00050001
    in which R ' 1 represents a group chosen from hydrogen atom, cyano group, hydroxymethylene group, carboxy group and linear or branched (C 1 -C 6 ) alkoxycarbonyl group,
    compound of formula (II) which is reacted under reductive amination conditions with a compound of formula (III) : (AO) 2 CHCHO (III) in which A represents a linear or branched (C 1 -C 6 ) alkyl group, to give compounds of formula (IV) :
    Figure 00060001
    in which A and R ' 1 are as defined above,
    compounds of formula (IV) which are treated with a compound of formula (V) : ClSO 2 E (V) in which E represents a linear or branched (C 1 -C 4 ) alkyl group, phenyl or p-toluyl, to yield compounds of formula (VI) :
    Figure 00060002
    in which A, E and R ' 1 are as defined above,
    compounds of formula (VI) which are cyclized under acidic conditions, to yield compounds of formula (VII) :
    Figure 00060003
    in which E and R ' 1 are as defined above,
    compounds of formula (VII) which are treated either with an alkali metal hydroxide in an alcoholic solvent or with sodium in liquid ammonia to yield compounds of formula (VIII) :
    Figure 00060004
    in which R ' 1 is as defined above,
    compounds of formula (VIII) which are then reduced according to conventional conditions of organic synthesis, to yield compounds of formula (IX):
    Figure 00070001
    in which R ' 1 is as defined above,
    compounds of formula (IX) which are treated with an isocyanate of formula ( X ): R 3 -N = C = O (X) in which R 3 is as defined in formula (I),
    to give compounds of formula (I / a) , in particular the compounds of formula (I):
    Figure 00070002
    in which R ' 1 and R 3 are as defined above,
    or compounds of formula (IX), in the particular case where R ' 1 represents a cyano group, which is treated:
    * Either with a ketone of formula (XI):
    Figure 00070003
    in which T has the same meanings as in formula (I), to give compounds of formula (XII) :
    Figure 00070004
    in which T is as defined previously,
    compounds of formula (XII) which are then:
    Figure 00070005
    either treated with an isocyanate of formula (X) as described above, to give compounds of formula (I / b), a particular case of compounds of formula (I),
    Figure 00080001
    in which T and R 3 are as defined above,
    or , after protection of the amine of the indoline group, reduced according to the conventional methods of organic synthesis, to yield compounds of formula (XIII) :
    Figure 00080002
    wherein T is as defined above and P 1 is a conventional protecting group,
    compounds of formula (XIII) whose primary amine function is then substituted and converted to secondary and tertiary amine function, using usual methods of organic chemistry, to yield compounds of formula (XIV) :
    Figure 00080003
    in which R 4 and R 5 have the same meanings as in formula (I) and, T and P 1 are as defined previously,
    compounds of formula (XIV) which, after deprotection of the nitrogen atom of the indoline ring, are treated with a compound of formula (X) as described above, to give compounds of formula (I / c) , a particular case compounds of formula (I):
    Figure 00090001
    in which T, R 4 , R 5 and R 3 are as defined above,
    or with a strong base or an alkali metal alkoxide, in the presence of a compound of formula (XV) : W 1 - X (XV) wherein W 1 represents an alkyl group (C 1 -C 6) linear or branched aryl- (C 1 -C 6) linear or branched, cycloalkyl, or cycloalkylalkyl (C 1 -C 6) linear or branched, and X represents a leaving group such as a halogen atom, a trifluoromethylsulfonate group, mesylate or tosylate group,
    to give compounds of formula (XVI) :
    Figure 00090002
    in which W 1 is as defined previously,
    compounds of formula (XVI) which are:
    are treated with a compound of formula (X) as described above, to give compounds of formula (I / d), a particular case of compounds of formula (I):
    Figure 00090003
    wherein W 1 and R 3 are as previously defined,
    is converted, after protection of the nitrogen atom of the indoline ring, as the compounds of formula (XII) into primary, secondary and then tertiary amine, to conduct after deprotection and treatment in the presence of a compound of formula (X) such as previously described, to the compounds of formula (I / e), a particular case of the compounds of formula (I):
    Figure 00100001
    in which W 1 , R 3 , R 4 and R 5 are as defined above,
    * Either with bromine in a chlorinated organic solvent, to yield compounds of formula (XVII):
    Figure 00100002
    compounds of formula (XVII) which are reacted with a compound of formula (XVIII) : W - V 1 - H (XVIII) in which W has the same meaning as in formula (I) and V 1 represents an oxygen atom or a sulfur atom,
    to give compounds of formula (XIX) :
    Figure 00100003
    in which V 1 and W are as defined above,
    compounds of formula (XIX) which are:
    or treated with a compound of formula (X) as described above, to give compounds of formula (I / f) , a particular case of compounds of formula (I):
    Figure 00110001
    in which R 3 , V 1 and W are as defined above,
    compounds of formula (I / f), in the particular case where V 1 represents a sulfur atom, which can be subjected to oxidation under conventional conditions of organic synthesis, to yield compounds of formula (I / g), particular case of the compounds of formula (I):
    Figure 00110002
    in which R 3 and W are as defined in formula (I) and q 1 is an integer between 1 and 2 inclusive,
    are protected and then converted, by the same sequence of reactions as the compounds of formula (XII), into primary, secondary and tertiary amines, to conduct after deprotection and treatment with a compound of formula (X), as described above, with the compounds of formula (I / h) , a particular case of the compounds of formula (I):
    Figure 00120001
    in which V 1 , W, R 3 , R 4 and R 5 are as defined above,
    compounds of formula (I / h) in the particular case where V 1 represents a sulfur atom, which may be subjected to oxidation under conventional conditions of organic synthesis, to yield compounds of formula (I / i) , case particular compounds of formula (I):
    Figure 00120002
    wherein W, R 3 , R 4 , R 5 and q 1 are as previously defined,
    or by an alkaline hydride in dimethylformamide in the presence of formaldehyde, to give compounds of formula (XX) :
    Figure 00120003
    compounds of formula (XX) which are:
    either treated with a compound of formula (X) as described above, to give compounds of formula (I / j), a particular case of compounds of formula (I):
    Figure 00130001
    in which R 3 is as defined in formula (I),
    are protected at the level of the nitrogen atom of the indoline nucleus and then treated according to the conditions of the Mitsunobu reaction with a compound of formula (XXI) : W - OH (XXI) in which W is as defined in formula (I),
    to conduct, after deprotection of the nitrogen atom of the indoline ring, to the compounds of formula (XXII) :
    Figure 00130002
    wherein W is as previously defined,
    compounds of formula (XXII) which are:
    Or treated with a compound of formula (X) as described above, to give compounds of formula (I / k) , a particular case of compounds of formula (I):
    Figure 00130003
    in which R 3 and W are as defined above,
    ◆ or protected and then converted, by the same reaction sequence as the compounds of formula (XII), primary amine, secondary and tertiary, to yield, after deprotection and treatment with a compound of formula (X), as described above, to compounds of formula (I / I) , particular case of compounds of formula (I):
    Figure 00140001
    in which R 3 , R 4 , R 5 and W are as defined above,
    the compounds (I / a) to (I / I) form all of the compounds of the invention which, if appropriate, are purified by a conventional purification technique which can, if desired, be separated in their different isomers according to a conventional separation technique, and which, if appropriate, are converted into their addition salts with a pharmaceutically acceptable acid or base.

    Les composés de formule (II), (III), (V), (X), (XI), (XV), (XVIII) et (XXI) sont soit des produits connus, soit des produits obtenus à partir de substances connues selon des procédés classiques de la chimie organique.The compounds of formula (II), (III), (V), (X), (XI), (XV), (XVIII) and (XXI) are either known products, ie products obtained from substances known to classical processes of organic chemistry.

    Les composés de la présente invention, de part leurs propriétés pharmacologiques, sont utiles, en tant que médicament, dans le traitement de l'anxiété, des attaques de panique, des troubles obsessionnels compulsifs, des phobies, des troubles impulsifs, de l'abus de drogue, des troubles de la cognition, des psychoses, des dépressions, et des troubles de l'humeur.The compounds of the present invention, by virtue of their pharmacological properties, are useful as a drug in the treatment of anxiety, panic attacks, obsessive-compulsive disorder, phobias, impulsive disorders, drug abuse, disorders of cognition, psychoses, depressions, and mood disorders.

    La présente invention a également pour objet les compositions pharmaceutiques contenant comme principe actif au moins un composé de formule (I), ses isomères optiques, ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, seul ou en combinaison avec un ou plusieurs excipients ou véhicules inertes, non toxiques, pharmaceutiquement acceptables.The subject of the present invention is also the pharmaceutical compositions containing as active ingredient at least one compound of formula (I), its optical isomers, its salts addition to a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic excipients or carriers, pharmaceutically acceptable.

    Parmi les compositions pharmaceutiques selon l'invention, il sera cité plus particulièrement celles qui conviennent pour l'administration orale, parentérale (intraveineuse, intramusculaire ou sous-cutanée), per ou transcutanée, nasale, rectale, perlinguale, oculaire ou respiratoire, et notamment les comprimés simples ou dragéifiés, les comprimés sublinguaux, les gélules, les capsules, les suppositoires, les crèmes, les pommades, les gels dermiques, les préparations injectables ou buvables, les aérosols, les gouttes oculaires ou nasales, etc...Among the pharmaceutical compositions according to the invention, it will be mentioned more particularly those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per or transcutaneous, nasal, rectal, perlingual, ocular or respiratory, and especially simple or sugar-coated tablets, tablets sublinguals, capsules, capsules, suppositories, creams, ointments, gels dermal, injectable or drinkable preparations, aerosols, eye drops or nasal, etc.

    La posologie utile varie selon l'âge et le poids du patient, la voie d'administration, la nature et la sévérité de l'affection, et la prise de traitements éventuels associés et s'échelonne de 0,5 mg à 25 mg en une ou plusieurs prises par jour.The dosage varies depending on the age and weight of the patient, the route of administration, the nature of and the severity of the condition, and the intake of any associated treatments and ranges from 0.5 mg to 25 mg in one or more doses per day.

    Les exemples suivants illustrent l'invention mais ne la limitent en aucune façon. Les produits de départ utilisés sont des produits connus ou préparés selon des modes opératoires connus. Les différentes préparations conduisent à des intermédiaires de synthèse utiles pour la préparation des composés de l'invention.The following examples illustrate the invention but do not limit it in any way. The starting materials used are known or known operating procedures. The different preparations lead to intermediates of synthesis useful for the preparation of the compounds of the invention.

    Les structures des composés décrits dans les exemples ont été déterminées selon les techniques spectrophotométriques usuelles (infrarouge, résonance magnétique nucléaire, spectrométrie de masse, ...).The structures of the compounds described in the examples were determined according to usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, ...).

    Les points de fusion ont été déterminés soit à la platine chauffante de Kofler (K.), soit à la platine chauffante sous microscope (M.K.). Lorsque le composé existe sous forme de sel, le point de fusion donné correspond à celui du produit salifié.The melting points were determined either on the Kofler heating stage (K.) or on the hot stage under microscope (M.K.). When the compound exists in salt form, the melting point given corresponds to that of the salified product.

    A titre indicatif, la numérotation adoptée pour les systèmes tricycliques est la suivante :

    Figure 00160001
    Figure 00160002
    As an indication, the numbering adopted for tricyclic systems is as follows:
    Figure 00160001
    Figure 00160002

    PREPARATION 1 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indole-6-carbonitrile PREPARATION 1 : 2,3,5,6-Tetrahydro- 1H- cyclobuta [ f ] indole-6-carbonitrile Stade 1 : 5-[(2,2-Diméthoxyéthyl)amino]benzocyclobutane-1-carbonitrileStep 1 : 5 - [(2,2-Dimethoxyethyl) amino] benzocyclobutane-1-carbonitrile

    Sur une suspension de 13,5 g de 5-amino-benzocyclobutane-1-carbonitrile dans 400 ml de 1,2-dichloroéthane sont ajoutés par un goutte à goutte rapide, 26,5 ml d'une solution de 2,2-diméthoxy-acétaldéhyde à 45 % dans le tertbutylméthyléther, puis 16 ml d'acide acétique, puis par fraction, 39,7 g de triacétoxyborohydrure de sodium. Après élévation de la température à 29°C, le milieu réactionnel est ramené à température ambiante, agité 1 h 15 puis hydrolysé en versant le milieu sur 500 ml d'une solution aqueuse saturée au NaHCO3. La phase organique est séparée, lavée à l'eau, et concentrée sous pression réduite pour conduire au produit désiré.A suspension of 13.5 g of 5-amino-benzocyclobutane-1-carbonitrile in 400 ml of 1,2-dichloroethane is added dropwise, 26.5 ml of a solution of 2,2-dimethoxy. 45% acetaldehyde in tert-butyl methyl ether, followed by 16 ml of acetic acid and then, by fraction, 39.7 g of sodium triacetoxyborohydride. After raising the temperature to 29 ° C, the reaction medium is brought to room temperature, stirred for 1 h 15 and then hydrolyzed by pouring the medium into 500 ml of an aqueous solution saturated with NaHCO 3 . The organic phase is separated, washed with water, and concentrated under reduced pressure to yield the desired product.

    Stade 2 : 5-[N-(2,2-Diméthoxyéthyl)-N-(méthylsulfonyl)amino]benzocyclobutane-1-carbonitrileStep 2 : 5- [N- (2,2-Dimethoxyethyl) -N- (methylsulfonyl) amino] benzocyclobutane-1-carbonitrile

    A une solution refroidie à 0°C de 21,6 g du produit obtenu au stade 1, 58 ml de pyridine et 225 ml de dichlorométhane sont ajoutés, en 20 minutes, 10,8 ml de chlorure de mésyle. Après 40 minutes d'agitation à 0°C puis 20 heures à température ambiante, le milieu réactionnel est versé sur 40 ml d'une solution aqueuse saturée en NaHCO3. Après décantation et extraction par 2 fois 150 ml de dichlorométhane, les phases organiques jointes sont lavées à l'acide chlorhydrique 1N, séchées puis concentrées sous pression réduite pour conduire au produit attendu.To a cooled solution at 0 ° C of 21.6 g of the product obtained in Stage 1, 58 ml of pyridine and 225 ml of dichloromethane are added, in 20 minutes, 10.8 ml of mesyl chloride. After stirring for 40 minutes at 0 ° C. and then for 20 hours at room temperature, the reaction medium is poured into 40 ml of a saturated aqueous solution of NaHCO 3 . After decantation and extraction with twice 150 ml of dichloromethane, the combined organic phases are washed with 1N hydrochloric acid, dried and concentrated under reduced pressure to yield the expected product.

    Stade 3 : 1-(Méthylsulfonyl)-5,6-dihydro-1H-cyclobuta[f]indole-6-carbonitrile Step 3 : 1- (Methylsulfonyl) -5,6-dihydro-1H-cyclobuta [f] indole-6-carbonitrile

    Sur 2,1 l de toluène à reflux sont coulés simultanément en 1 h 15, une solution de 10,9 ml de chlorure de titane dans 450 ml de toluène et une solution de 27,9 g du produit obtenu au stade 2 dans 450 ml de toluène. A la fin de l'addition, on laisse redescendre la température jusqu'à 40°C, puis verse sur 1,8 l d'une solution aqueuse saturée en NaHCO3. Après décantation, la phase aqueuse est extraite au toluène, les phases organiques sont réunies, lavées, séchées et concentrées. Le résidu est purifié par chromatographie sur gel de silice (dichlorométhane/cyclohexane: 75/25) permettant d'isoler le produit attendu ainsi que son régioisomère.
    Point de fusion : 142-144°C (M.K.)     2.1 l of refluxing toluene are cast simultaneously in 1 h 15, a solution of 10.9 ml of titanium chloride in 450 ml of toluene and a solution of 27.9 g of the product obtained in stage 2 in 450 ml toluene. At the end of the addition, the temperature is allowed to drop to 40 ° C. and poured onto 1.8 l of a saturated aqueous solution of NaHCO 3 . After decantation, the aqueous phase is extracted with toluene, the organic phases are combined, washed, dried and concentrated. The residue is purified by chromatography on silica gel (dichloromethane / cyclohexane: 75/25) to isolate the expected product and its regioisomer.
    Melting point : 142-144 ° C (MK)

    Stade 4 : 5,6-Dihydro-1H-cyclobuta[f]indole-6-carbonitrileStep 4 : 5,6-Dihydro-1H-cyclobuta [f] indole-6-carbonitrile

    2,6 g du produit obtenu au stade 3 sont introduits dans une solution de 7,7 g de potasse dans 190 ml de méthanol. Après 12 heures à reflux, le méthanol est évaporé et le résidu repris par de l'éther. Après lavage, la phase organique est séchée et concentrée pour conduire au produit attendu.
    Point de fusion : 126-128°C (M.K.)     2.6 g of the product obtained in Step 3 are introduced into a solution of 7.7 g of potassium hydroxide in 190 ml of methanol. After 12 hours at reflux, the methanol is evaporated and the residue taken up in ether. After washing, the organic phase is dried and concentrated to yield the expected product.
    Melting point : 126-128 ° C (MK)

    Stade 5 : 2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-6-carbonitrileStep 5 : 2,3,5,6-Tetrahydro-1H-cyclobuta [f] indole-6-carbonitrile

    3,43 g du produit obtenu au stade 4 sont solubilisés dans 55 ml d'acide acétique. Dans le milieu réactionnel refroidi à 13°C, sont ajoutés, par portions, en 5 minutes, 3,84 g de cyanoborohydrure de sodium. Après retour à température ambiante, l'agitation est maintenue pendant 2 heures, puis le milieu réactionnel est refroidi à 0°C et amené à pH = 11 par addition d'une solution de soude (45 g dans 250 ml d'eau). La solution laiteuse obtenue est extraite à l'éther. Les phases organiques sont lavées, séchées et concentrées pour conduire au produit attendu.
    Point de fusion : 85-87°C (M.K.)     3.43 g of the product obtained in stage 4 are solubilized in 55 ml of acetic acid. In the reaction medium cooled to 13 ° C., 3.84 g of sodium cyanoborohydride are added, in portions, in the course of 5 minutes. After returning to ambient temperature, the stirring is maintained for 2 hours, then the reaction medium is cooled to 0 ° C. and brought to pH = 11 by addition of a sodium hydroxide solution (45 g in 250 ml of water). The milky solution obtained is extracted with ether. The organic phases are washed, dried and concentrated to yield the expected product.
    Melting point : 85-87 ° C (MK)

    PREPARATION 2 : 2,3,6,7-Tétrahydro-1H-cyclobuta[e]indole-7-carbonitrile PREPARATION 2 : 2,3,6,7-Tetrahydro- 1H- cyclobuta [ e ] indole-7-carbonitrile Stade 1 : 6,7-Dihydro-3H-cyclobuta[e]indole-7-carbonitrileStep 1 : 6,7-Dihydro-3H-cyclobuta [e] indole-7-carbonitrile

    Le produit est obtenu selon le procédé du stade 4 de la préparation 1 en utilisant comme substrat le régioisomère obtenu au stade 3 de la préparation 1.The product is obtained according to the process of Stage 4 of Preparation 1 using as substrate the regioisomer obtained in Step 3 of Preparation 1.

    Stade 2 : 2,3,6,7-Tétrahydro-1H-cyclobuta[e]indole-7-carbonitrileStep 2 : 2,3,6,7-Tetrahydro-1H-cyclobuta [e] indole-7-carbonitrile

    Le produit est obtenu, à partir du composé obtenu au stade 1, selon le procédé du stade 5 de la préparation 1.The product is obtained from the compound obtained in stage 1, according to the method of stage 5 of preparation 1.

    PREPARATION 3 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indole PREPARATION 3 : 2,3,5,6-Tetrahydro- 1H- cyclobuta [ f ] indole Stade 1 : 4-[(2,2-Diméthoxyéthyl)amino]benzocyclobutaneStep 1 : 4 - [(2,2-Dimethoxyethyl) amino] benzocyclobutane

    Une solution de 1 g du produit obtenu au stade 1 de la préparation 1, dans 20 ml de tétrahydrofurane et 0,22 ml d'éthanol anhydre est ajoutée, à -70°C, à 40 ml d'ammoniac liquide. 322 mg de sodium sont alors ajoutés par portions, et l'agitation est maintenue à -70°C pendant 20 minutes. La réaction est stoppée par addition de 1,72 g de NH4Cl, et on laisse tout l'ammoniac s'évaporer. Le milieu réactionnel est repris par une solution saturée en NH4Cl puis extrait à l'éther. La phase organique est ensuite séchée puis concentrée pour conduire au produit attendu.A solution of 1 g of the product obtained in Stage 1 of Preparation 1, in 20 ml of tetrahydrofuran and 0.22 ml of anhydrous ethanol is added, at -70 ° C., to 40 ml of liquid ammonia. 322 mg of sodium are then added in portions, and stirring is maintained at -70 ° C for 20 minutes. The reaction is stopped by addition of 1.72 g of NH 4 Cl, and all the ammonia is allowed to evaporate. The reaction medium is taken up in a saturated solution of NH 4 Cl and then extracted with ether. The organic phase is then dried and concentrated to yield the expected product.

    Stade 2 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indole Stage 2 : 2,3,5,6-Tetrahydro-1H-cyclobuta [f] indole

    Le produit est obtenu selon le procédé de la préparation 1, des stades 2 à 5.
    Point de fusion : 68-70°C     The product is obtained according to the process of Preparation 1, Steps 2 to 5.
    Melting point : 68-70 ° C

    PREPARATION 4 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indol-6-ylméthanol PREPARATION 4 : 2,3,5,6-Tetrahydro- 1H- cyclobuta [ f ] indol-6-ylmethanol Stade 1 : 5-Amino-1-benzocyclobutanecarboxylate de méthyle Stage 1 : Methyl 5-Amino-1-benzocyclobutanecarboxylate

    9,74 g de 5-nitro-1-benzocyclobutanecarboxylate de méthyle sont mis à hydrogéner, à température ambiante et pression atmosphérique, en présence de Pd/C à 10 % pendant 6 h 30. Après filtration et concentration sous pression réduite, le produit attendu est isolé.9.74 g of methyl 5-nitro-1-benzocyclobutanecarboxylate are allowed to hydrogenate, to room temperature and atmospheric pressure, in the presence of 10% Pd / C for 6 h 30. After filtration and concentration under reduced pressure, the expected product is isolated.

    Stade 2 : 5-[(2,2-Diméthoxyéthyl)amino]-1-benzocyclobutanecarboxylate de méthyle Stage 2 : Methyl 5 - [(2,2-Dimethoxyethyl) amino] -1-benzocyclobutanecarboxylate

    Le produit est obtenu, à partir du composé du stade précédent, selon le procédé du stade 1 de la préparation 1.The product is obtained from the compound of the previous stage, according to the method of stage 1 of preparation 1.

    Stade 3 : 5-[N-(2,2-Diméthoxyéthyl)-N-(méthylsulfonyl)amino]-1-benzocyclobutanecarboxylate de méthyleStep 3 : Methyl 5- [N- (2,2-dimethoxyethyl) -N- (methylsulfonyl) amino] -1-benzocyclobutanecarboxylate

    Le produit est obtenu, à partir du composé du stade précédent, selon le procédé du stade 2 de la préparation 1.The product is obtained from the compound of the previous stage, according to the method of stage 2 of preparation 1.

    Stade 4 : 1-(Méthylsulfonyl)-5,6-dihydro-1H-cyclobuta[f]indole-6-carboxylate de méthyle Step 4 : Methyl 1- (methylsulfonyl) -5,6-dihydro-1H-cyclobuta [f] indole-6-carboxylate

    Le produit est obtenu, à partir du composé du stade précédent, selon le procédé du stade 3 de la préparation 1.The product is obtained from the compound of the previous stage, according to the method of stage 3 of preparation 1.

    Stade 5 : [1-(Méthylsulfonyl)-5,6-dihydro-1H-cyclobuta[f]indol-6-yl]méthanol Step 5 : [1- (Methylsulfonyl) -5,6-dihydro-1H-cyclobuta [f] indol-6-yl] methanol

    Sur une suspension de 0,42 g d'hydrure de lithium et aluminium dans 7 ml de tétrahydrofurane, maintenue à 0°C, est ajoutée, goutte à goutte, une solution de 1,6 g du produit obtenu au stade 4 dans 20 ml de tétrahydrofurane. Après 20 minutes, le milieu réactionnel est hydrolysé par 0,3 ml d'eau, 0,23 ml de soude à 20 %, puis 1,05 ml d'eau. Après filtration des sels, le filtrat est concentré sous pression réduite pour conduire au produit attendu.On a suspension of 0.42 g of lithium aluminum hydride in 7 ml of tetrahydrofuran, maintained at 0 ° C., is added, dropwise, a solution of 1.6 g of product obtained in Step 4 in 20 ml of tetrahydrofuran. After 20 minutes, the middle The reaction mixture is hydrolysed with 0.3 ml of water, 0.23 ml of 20% sodium hydroxide and then 1.05 ml of water. After filtration of the salts, the filtrate is concentrated under reduced pressure to yield the expected product.

    Stade 6 : 5,6-Dihydro-1H-cyclobuta[f]indol-6-ylmethanolStep 6 : 5,6-Dihydro-1H-cyclobuta [f] indol-6-ylmethanol

    Le produit est obtenu, à partir du composé du stade précédent, selon le procédé du stade 4 de la préparation 1.The product is obtained from the compound of the previous stage, according to the process of stage 4 of preparation 1.

    Stade 7 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indol-6-ylméthanolStep 7 : 2,3,5,6-Tetrahydro-1H-cyclobuta [f] indol-6-ylmethanol

    Le produit est obtenu, à partir du composé du stade précédent, selon le procédé du stade 5 de la préparation 1. Le composé est isolé après une chromatographie sur gel de silice (dichlorométhane/éthanol : 97/3).The product is obtained from the compound of the preceding stage, according to the process of stage 5 of the preparation 1. The compound is isolated after silica gel chromatography (dichloromethane / ethanol: 97/3).

    PREPARATION 5 : 2,3,6,7-Tétrahydro-1H-cyclobuta[g]indol-7-ylméthanol PREPARATION 5 : 2,3,6,7-Tetrahydro- 1H- cyclobuta [ g ] indol-7-ylmethanol Stade 1 : 6-Acétyl-1-benzocyclobutanecarbonitrile Step 1 : 6-Acetyl-1-benzocyclobutanecarbonitrile

    Une solution composée de 55,94 g de 6-trifluoroacétyl-1-benzocyclobutanecarbonitrile dans 600 ml de pyridine est dégazée à l'azote pendant 15 minutes ; 30,5 ml de triéthylamine, 117,44 ml de butylvinyléther, 2,25 g de 1,3-bis-(diphénylphosphino)propane et 1,02 g d'acétate de palladium sont ajoutés et le milieu réactionnel est porté au reflux pendant 2 heures. 400 ml d'acide chlorhydrique 1N sont ensuite introduits goutte à goutte en 1 heure, et après 3 heures d'agitation à température ambiante, le milieu réactionnel est extrait à l'éther. Les phases organiques sont lavées, séchées et concentrées pour conduire à un résidu qui est purifié par chromatographie sur gel de silice (dichlorométhane : 100 %) permettant d'isoler le produit attendu.
    Point de fusion : 55-59°C     A solution consisting of 55.94 g of 6-trifluoroacetyl-1-benzocyclobutanecarbonitrile in 600 ml of pyridine is degassed with nitrogen for 15 minutes; 30.5 ml of triethylamine, 117.44 ml of butylvinyl ether, 2.25 g of 1,3-bis (diphenylphosphino) propane and 1.02 g of palladium acetate are added and the reaction mixture is refluxed for 2 hours. 400 ml of 1N hydrochloric acid are then introduced dropwise over 1 hour, and after stirring for 3 hours at room temperature, the reaction medium is extracted with ether. The organic phases are washed, dried and concentrated to give a residue which is purified by chromatography on silica gel (dichloromethane: 100%) to isolate the expected product.
    Melting point : 55-59 ° C

    Stade 2 : 6-Hydroxyiminoéthyl-1-benzocyclobutanecarbonitrileStep 2 : 6-Hydroxyiminoethyl-1-benzocyclobutanecarbonitrile

    10,07 g du produit du stade 1 et 6,13 g de chlorhydrate d'hydroxylamine dans 200 ml de pyridine sont agités à température ambiante pendant 19 heures. Après évaporation de la pyridine, l'huile jaune obtenue est reprise par du dichlorométhane et de l'eau. La phase organique est séparée, séchée et concentrée permettant d'isoler le produit attendu.
    Point de fusion : 108-110°C     10.07 g of the product of stage 1 and 6.13 g of hydroxylamine hydrochloride in 200 ml of pyridine are stirred at room temperature for 19 hours. After evaporation of the pyridine, the yellow oil obtained is taken up in dichloromethane and water. The organic phase is separated, dried and concentrated to isolate the expected product.
    Melting point : 108-110 ° C

    Stade 3 : N-(1-Cyanobenzocyclobutan-6-yl)acétamideStep 3 : N- (1-Cyanobenzocyclobutan-6-yl) acetamide

    A une solution de 8,9 g du produit obtenu au stade 2 dans 160 ml d'éther, refroidie à 0°C, sont ajoutés en quatre fois 9,96 g de PCl5. Après 2 heures d'agitation à 0°C, le milieu réactionnel est ramené à température ambiante pendant 12 heures, puis versé sur un mélange eau/glace et agité pendant 20 minutes. Après décantation et extraction à l'éther, les phases organiques réunies sont séchées puis concentrées sous pression réduite pour conduire au produit attendu.
    Point de fusion : < 50°C     To a solution of 8.9 g of the product obtained in Stage 2 in 160 ml of ether, cooled to 0 ° C, are added in four folds 9.96 g of PCl 5 . After stirring for 2 hours at 0 ° C., the reaction medium is brought back to ambient temperature for 12 hours, then poured into a water / ice mixture and stirred for 20 minutes. After decantation and extraction with ether, the combined organic phases are dried and then concentrated under reduced pressure to yield the expected product.
    Melting point : <50 ° C

    Stade 4 : 6-Amino-1-benzocyclobutanecarboxylate d'éthyle Stage 4 : 6-Amino-1-benzocyclobutanecarboxylate

    Un courant d'HCl gazeux est introduit jusqu'à saturation d'une solution de 5,04 g du produit obtenu au stade 3 dans 400 ml d'éthanol anhydre à 0°C. Le milieu réactionnel est ensuite porté à reflux pendant 18 heures. Après concentration du solvant, le résidu est repris à l'eau glacée, basifié par une solution de carbonate de sodium et extrait au dichlorométane. La phase organique est séparée, séchée et concentrée pour obtenir le produit attendu.A stream of gaseous HCl is introduced until saturation of a solution of 5.04 g of product obtained in Step 3 in 400 ml of anhydrous ethanol at 0 ° C. The reaction medium is then refluxed for 18 hours. After concentration of the solvent, the residue is taken up in iced water, basified with sodium carbonate solution and extracted with dichlorométane. The organic phase is separated, dried and concentrated to obtain the expected product.

    Stade 5 : 2,3,6,7-Tétrahydro-1H-cyclobuta[g]indol-7-ylméthanolStep 5 : 2,3,6,7-Tetrahydro-1H-cyclobuta [g] indol-7-ylmethanol

    Le produit est obtenu, à partir du composé du stade précédent, selon les procédés des stades 2 à 7 de la préparation 4.The product is obtained from the compound of the previous stage according to the processes of the stages 2 to 7 of preparation 4.

    PREPARATION 6 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indole-5-carbonitrile PREPARATION 6 : 2,3,5,6-Tetrahydro- 1H- cyclobuta [ f ] indole-5-carbonitrile

    Le produit est obtenu selon le procédé de la préparation 1, des stades 1 à 5, en utilisant comme substrat au stade 1 le 4-amino-1-benzocyclobutanecarbonitrile.
    Point de fusion : 103-107°C     The product is obtained according to the process of Preparation 1, Steps 1 to 5, using as substrate in Step 1 4-amino-1-benzocyclobutanecarbonitrile.
    Melting point : 103-107 ° C

    PREPARATION 7 : 2,3,5,6-Tétrahydro-1H-cyclobuta[f]indol-5-ylmethanol PREPARATION 7 : 2,3,5,6-Tetrahydro- 1H- cyclobuta [ f ] indol-5-ylmethanol

    Le produit est obtenu selon le procédé de la préparation 4, des stades 1 à 7, en utilisant comme substrat au stade 1 le 4-nitro-1-benzocyclobutanecarboxylate d'éthyle.The product is obtained according to the process of Preparation 4, Steps 1 to 7, using Ethyl 4-nitro-1-benzocyclobutanecarboxylate is a substrate in Step 1.

    PREPARATION 8 : Nicotinoyl azide PREPARATION 8 Nicotinoyl azide

    Sur une suspension de 12,3 g d'acide nicotinique dans 100 ml de diméthylformamide, 14,2 ml de triéthylamine sont additionnés, puis après refroidissement à 0°C, 22 ml de diphénylphosphorylazide dans 50 ml de diméthylformamide sont ajoutés. Après 2 heures d'agitation, le milieu réactionnel est coulé sur de la glace. Après extraction à l'éther, la phase organique est lavée avec une solution de NaHCO3, séchée puis concentrée pour donner 9,68 g du produit attendu.On a suspension of 12.3 g of nicotinic acid in 100 ml of dimethylformamide, 14.2 ml of triethylamine are added, then after cooling to 0 ° C, 22 ml of diphenylphosphorylazide in 50 ml of dimethylformamide are added. After stirring for 2 hours, the reaction medium is poured on ice. After extraction with ether, the organic phase is washed with a solution of NaHCO 3 , dried and concentrated to give 9.68 g of the expected product.

    PREPARATION 9 : Phényl 6-[(2-méthyl-3-pyridinyl)oxy]-3-pyridinylcarbamate PREPARATION 9 Phenyl 6 - [(2-methyl-3-pyridinyl) oxy] -3-pyridinylcarbamate Stade 1 : 6-[(2-Méthyl-3-pyridinyl)oxy]-3-pyridinylamine Step 1 : 6 - [(2-Methyl-3-pyridinyl) oxy] -3-pyridinylamine

    Une solution de 14,35 g de chlorure d'étain dans 30 ml d'acide chlorhydrique concentré est ajoutée à un mélange de 5 g de 2-(2-méthylpyridi-3-yloxy)5-nitropyridine et portée à reflux pendant 1 heure. Le milieu réactionnel est refroidi et amené à pH basique par addition de soude concentré. Après filtration d'un précipité, la phase aqueuse est extraite à l'acétate d'éthyle. Après traitement usuel, le produit attendu est isolé sous la forme d'une poudre violette.
    Point de fusion : 95-100°C (M.K.)     A solution of 14.35 g of tin chloride in 30 ml of concentrated hydrochloric acid is added to a mixture of 5 g of 2- (2-methylpyrid-3-yloxy) -5-nitropyridine and refluxed for 1 hour. . The reaction medium is cooled and brought to basic pH by addition of concentrated sodium hydroxide. After filtration of a precipitate, the aqueous phase is extracted with ethyl acetate. After usual treatment, the expected product is isolated in the form of a violet powder.
    Melting point : 95-100 ° C (MK)

    Stade 2 : Phényl 6-[(2-méthyl-3-pyridinyl)oxy]-3-pyridinylcarbamateStep 2 : Phenyl 6 - [(2-methyl-3-pyridinyl) oxy] -3-pyridinylcarbamate

    3 ml de chloroformiate de méthyle sont ajoutés goutte à goutte sur une solution de 4,5 g du produit obtenu au stade 1, 3,3 ml de triéthylamine et 180 ml de dichlorométhane, maintenue à -20°C. Après retour à température ambiante, le milieu réactionnel est lavé au bicarbonate de sodium, séché et concentré sous pression réduite. Une chromatographie sur gel de silice du résidu (dicholrométhane/éthanol/NH4OH : 98/2/0,29) permet d'isoler le produit attendu.3 ml of methyl chloroformate are added dropwise to a solution of 4.5 g of the product obtained in Stage 1, 3.3 ml of triethylamine and 180 ml of dichloromethane, maintained at -20 ° C. After returning to ambient temperature, the reaction medium is washed with sodium bicarbonate, dried and concentrated under reduced pressure. Chromatography on silica gel of the residue (dicholomethane / ethanol / NH 4 OH: 98/2 / 0.29) makes it possible to isolate the expected product.

    EXEMPLE 1 : N-(3-Pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 1 N- (3-Pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide

    7,4 g du composé de la préparation 8 dans 40 ml de toluène sont portés à reflux pendant 2 h 30, puis refroidis à température ambiante. 0,99 g du produit de la préparation 3 dissout dans 50 ml de dichlorométhane sont alors introduits goutte à goutte. Après 18 heures d'agitation, le milieu réactionnel est filtré, et le filtrat est concentré sous pression réduite. Une chromatographie sur gel de silice (dichlorométhane/éthanol : 95/5) permet d'isoler le produit attendu qui est ensuite recristallisé de l'éthanol.
    Point de fusion : 178-180°C (M.K.)     7.4 g of the compound of Preparation 8 in 40 ml of toluene are refluxed for 2 h 30 and then cooled to room temperature. 0.99 g of the product of Preparation 3 dissolved in 50 ml of dichloromethane are then introduced dropwise. After stirring for 18 hours, the reaction medium is filtered and the filtrate is concentrated under reduced pressure. Chromatography on silica gel (dichloromethane / ethanol: 95/5) makes it possible to isolate the expected product which is then recrystallized from ethanol.
    Melting point : 178-180 ° C (MK)

    EXEMPLE 2 : 6-(Hydroxyméthyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta [f]indole-1-carboxamide EXAMPLE 2 6- (Hydroxymethyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1 en utilisant comme substrat le composé de la préparation 4.
    Point de fusion : 195-200°C (M.K.)     The product is obtained according to the method of Example 1, using as substrate the compound of Preparation 4.
    Melting point : 195-200 ° C (MK)

    EXEMPLE 3 : 6-Cyano-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 3 6-Cyano-N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1 en utilisant comme substrat le composé de la préparation 1.
    Point de fusion : 203-207°C (M.K.)     The product is obtained according to the method of Example 1, using as substrate the compound of Preparation 1.
    Melting point : 203-207 ° C (MK)

    EXEMPLE 4 : 5-Cyano-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 4 5-Cyano-N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1 en utilisant comme substrat le composé de la préparation 6.
    Point de fusion : 209-211°C (M.K.)     The product is obtained according to the method of Example 1, using as substrate the compound of Preparation 6.
    Melting point : 209-211 ° C (MK)

    EXEMPLE 5 : 5-(Hydroxyméthyl)-N-(3-pyridinyl)-2,3,5,6-tetrahydro-1H-cyclobuta [f]indole-1-carboxamide EXAMPLE 5 5- (Hydroxymethyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1 en utilisant comme substrat le composé de la préparation 7.
    Point de fusion : 167-173°C (M.K.)     The product is obtained according to the method of Example 1, using as substrate the compound of Preparation 7.
    Melting point : 167-173 ° C (MK)

    EXEMPLE 6 : 7-Cyano-N-(3-pyridinyl)-1,2,6,7-tétrahydro-3H-cyclobuta[e]indole-3-carboxamide EXAMPLE 6 7-Cyano-N- (3-pyridinyl) -1,2,6,7-tetrahydro-3 H -cyclobuta [e] indole-3-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1 en utilisant comme substrat le composé de la préparation 2.
    Point de fusion : 203-205°C (M.K.)     The product is obtained according to the method of Example 1, using as substrate the compound of Preparation 2.
    Melting point : 203-205 ° C (MK)

    EXEMPLE 7 : 7-(Hydroxyméthyl)-N-(3-pyridinyl)-2,3,6,7-tétrahydro-1H-cyclobuta [g]indole-1-carboxamide EXAMPLE 7 : 7- (Hydroxymethyl) -N- (3-pyridinyl) -2,3,6,7-tetrahydro- 1H- cyclobuta [ g ] indole-1-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1 en utilisant comme substrat le composé de la préparation 5.
    Point de fusion : 216-220°C (M.K.)     The product is obtained according to the method of Example 1, using as substrate the compound of Preparation 5.
    Melting point : 216-220 ° C (MK)

    EXEMPLE 8 : 6-[(Diméthylamino)méthyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 8 6 - [(Dimethylamino) methyl] -6- (1-hydroxycyclohexyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide Stade 1 : 6-(1-Hydroxycyclohexyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-6-carbonitrileStep 1 : 6- (1-Hydroxycyclohexyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-6-carbonitrile

    4,1 g du produit obtenu à la préparation 1 sont dissous dans 215 ml de tétrahydrofurane. Le milieu réactionnel est refroidi à -80°C et 19,25 ml d'une solution 2,5 M de n-butyllithium dans l'hexane sont additionnés par l'intermédiaire d'un pousse-seringue. A la fin de l'addition, l'agitation est maintenue 20 minutes puis 6,2 ml de cyclohexanone sont coulés en 3 minutes. Après 2 heures de contact à -80°C, on laisse revenir à température ambiante et introduit 23 ml d'une solution aqueuse saturée de chlorure d'ammonium et encore 135 ml d'eau. Après décantation, la phase organique est lavée par une solution saturée de chlorure de sodium, séchée, concentrée. Le résidu obtenu est concrétisé de l'éther isopropylique, filtré pour obtenir le produit désiré et le filtrat est purifié par chromatographie sur gel de silice (CH2Cl2/AcOEt : 90/10) pour isoler une quantité supplémentaire de produit attendu.
    Point de fusion : 168-170°C     4.1 g of the product obtained in Preparation 1 are dissolved in 215 ml of tetrahydrofuran. The reaction medium is cooled to -80 ° C. and 19.25 ml of a 2.5 M solution of n-butyllithium in hexane are added via a syringe pump. At the end of the addition, the stirring is maintained for 20 minutes and then 6.2 ml of cyclohexanone are cast in 3 minutes. After 2 hours of contact at -80 ° C., it is allowed to return to room temperature and 23 ml of a saturated aqueous solution of ammonium chloride and another 135 ml of water are introduced. After decantation, the organic phase is washed with a saturated solution of sodium chloride, dried, concentrated. The residue obtained is crystallized from isopropyl ether, filtered to obtain the desired product and the filtrate is purified by chromatography on silica gel (CH 2 Cl 2 / AcOEt: 90/10) to isolate an additional quantity of expected product.
    Melting point : 168-170 ° C

    Stade 2 : 6-(1-Hydroxycyclohexyl)-1-(méthylsulfonyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-6-carbonitrile Step 2 : 6- (1-Hydroxycyclohexyl) -1- (methylsulfonyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-6-carbonitrile

    4 g du produit obtenu au stade 1 sont mis en réaction dans les conditions du stade 2 de la préparation 1.4 g of the product obtained in stage 1 are reacted under the conditions of stage 2 of the preparation 1.

    Stade 3 : 1-[6-(Aminométhyl)-1-(méthylsulfonyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indol-6-yl]cyclohexanolStep 3 : 1- [6- (Aminomethyl) -1- (methylsulfonyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indol-6-yl] cyclohexanol

    5,5 g du produit obtenu au stade 2 sont dissous dans 250 ml d'une solution 3,6 N de méthanol ammoniacal contenant 2 mg de nickel de Raney. Le mélange réactionnel est hydrogéné sous une pression de 30 bars à 60°C pendant 24 heures. Après filtration et évaporation du solvant, le résidu est repris par du dichlorométhane, lavé à l'eau à neutralité, séché et concentré pour isoler le produit attendu. 5.5 g of the product obtained in stage 2 are dissolved in 250 ml of a 3.6 N solution of ammonia methanol containing 2 mg of Raney nickel. The reaction mixture is hydrogenated under a pressure of 30 bar at 60 ° C for 24 hours. After filtration and evaporation of the solvent, the residue is taken up in dichloromethane, washed with water to neutrality, dried and concentrated to isolate the expected product.

    Stade 4 : 1-[6-[(Diméthylamino)méthyl]-1-(méthylsulfonyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indol-6-yl]cyclohexanol Step 4 : 1- [6 - [(Dimethylamino) methyl] -1- (methylsulfonyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indol-6-yl] cyclohexanol

    5,37 g de l'amine obtenue au stade 3 sont dissous dans 130 ml d'acétonitrile. Dans la solution refroidie à 0°C, 2,9 g de cyanoborohydrure de sodium et 6,9 ml d'une solution de formaldéhyde à 37 % dans l'eau sont introduits en maintenant la température à 0°C. Après 20 heures de réaction à température ambiante, le milieu est hydrolysé par 210 ml d'acide chlorhydrique 1N puis agité 3 heures. Le mélange réactionnel est lavé avec 30 ml d'éther puis basifié par de la soude à 20 %. La phase aqueuse est extraite au dichlorométhane. Après séchage et évaporation, le résidu est purifié par chromatographie sur gel de silice (CH2Cl2/EtOH : 95/5) pour conduire au produit attendu.
    Point de fusion : 156-158°C (M.K.)     5.37 g of the amine obtained in stage 3 are dissolved in 130 ml of acetonitrile. In the cooled solution at 0 ° C., 2.9 g of sodium cyanoborohydride and 6.9 ml of a 37% formaldehyde solution in water are introduced while maintaining the temperature at 0 ° C. After 20 hours of reaction at ambient temperature, the medium is hydrolysed with 210 ml of 1N hydrochloric acid and then stirred for 3 hours. The reaction mixture is washed with 30 ml of ether and then basified with 20% sodium hydroxide. The aqueous phase is extracted with dichloromethane. After drying and evaporation, the residue is purified by chromatography on silica gel (CH 2 Cl 2 / EtOH 95/5) to yield the expected product.
    Melting point : 156-158 ° C (MK)

    Stade 5 : 1-{6-[(Diméthylamino)méthyl]-2,3,5,6-tétrahydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol Step 5 : 1- {6 - [(Dimethylamino) methyl] -2,3,5,6-tetrahydro-1H-cyclobuta [f] indol-6-yl} cyclohexanol

    3,75 g du produit obtenu au stade 4 dans 100 ml de tétrahydrofurane sont ajoutés goutte à goutte sur 400 ml d'ammoniac liquide refroidi à -50°C. 0,56 g de sodium sont ajoutés par portions et l'agitation est maintenue durant 15 minutes. La réaction est stoppée par addition de 2,65 g de chlorure d'ammonium. On laisse revenir à température ambiante pour évaporer l'ammoniac puis reprend par de l'eau et extrait à l'éther. On sèche, évapore et recristallise de l'acétonitrile pour conduire au produit attendu.
    Point de fusion : 159-161°C (M.K.)     3.75 g of the product obtained in Stage 4 in 100 ml of tetrahydrofuran are added dropwise to 400 ml of liquid ammonia cooled to -50 ° C. 0.56 g of sodium are added portionwise and stirring is continued for 15 minutes. The reaction is stopped by the addition of 2.65 g of ammonium chloride. Allowed to warm to room temperature to evaporate the ammonia and then taken up with water and extracted with ether. Dry, evaporate and recrystallize acetonitrile to yield the expected product.
    Melting point : 159-161 ° C (MK)

    Stade 6 : 6-[(Diméthylamino)méthyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide Step 6 : 6 - [(Dimethylamino) methyl] -6- (1-hydroxycyclohexyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide

    Le produit est obtenu selon le procédé de l'exemple 1, en utilisant comme substrat le produit obtenu au stade 5.
    Point de fusion : 207-209°C     The product is obtained according to the method of Example 1, using as substrate the product obtained in Step 5.
    Melting point : 207-209 ° C

    EXEMPLE 9 : 6-Cyano-6-(phénylsulfanyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 9 6-Cyano-6- (phenylsulfanyl) - N - (3-pyridinyl) -2,3,5,6-tetrahydro-1 H -cyclobuta [f] indole-1-carboxamide Stade 1 : 6-(Phénylsulfanyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole 6-carbonitrileStep 1 : 6- (Phenylsulfanyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole 6-carbonitrile

    A une solution de 2 g du produit de la préparation 1 dissout dans 40 ml de tétrahydrofurane, refroidie à -70°C sont ajoutés en 30 minutes 15 ml d'une solution 1,6 N de n-butyllithium dans l'hexane, puis 2,82 g de diphénylsulfure dissous dans 8 ml de tétrahydrofurane sont coulés. Le milieu réactionnel est ramené lentement à température ambiante. Après 2 heures de réaction, le milieu est versé sur 1,2 1 d'une solution saturée en chlorure d'ammonium puis extrait à l'éther. Les phases organiques réunies sont purifiées par passage acido-basique, permettant d'isoler le produit attendu.To a solution of 2 g of the product of Preparation 1 dissolved in 40 ml of tetrahydrofuran, cooled to -70 ° C., 15 ml of a 1.6 N solution of n- butyllithium in hexane are added over 30 minutes. 2.82 g of diphenylsulphide dissolved in 8 ml of tetrahydrofuran are cast. The reaction medium is slowly brought to ambient temperature. After 2 hours of reaction, the medium is poured into 1.2 l of saturated ammonium chloride solution and then extracted with ether. The combined organic phases are purified by acid-base passage, to isolate the expected product.

    Stade 2 : 6-Cyano-6-(phénylsulfanyl)-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide Step 2 : 6-Cyano-6- (phenylsulfanyl) -N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide

    0,43 g du produit obtenu au stade 1 sont traités par 0,297 g du composé de la préparation 8, selon le procédé décrit à l'exemple 1, permettant d'obtenir le produit attendu.
    Point de fusion : 110-113°C (M.K.)    0.43 g of the product obtained in Stage 1 are treated with 0.297 g of the compound of Preparation 8, according to the process described in Example 1, to obtain the expected product.
    Melting point: 110-113 ° C (MK)

    EXEMPLE 10 : 6-Cyano-6-cyclohéxyl-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 10 6-Cyano-6-cyclohexyl N - (3-pyridinyl) -2,3,5,6-tetrahydro-1 H -cyclobuta [f] indole-1-carboxamide Stade 1 : 6-cyclohéxyl-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole 6-carbonitrileStep 1 : 6-cyclohexyl-2,3,5,6-tetrahydro-1H-cyclobuta [f] indole 6-carbonitrile

    A une solution de 2 g du produit de la préparation 1 dissout dans 20 ml de tétrahydrofurane, refroidie à -70°C sont ajoutés en 30 minutes 15 ml d'une solution 1,6 N de n-butyllithium dans l'hexane. Après 30 minutes de contact, 2,17 ml de bromocyclohexane sont coulé »s en 25 minutes et le milieu réactionnel est progressivement ramené à -20°C puis versé sur une solution saturée de chlorure d'ammonium et enfin extrait à l'éther. Une purification sur silice (dichlorométhane/acétate d'éthyle : 95/5) conduit au produit attendu sous forme d'huile.To a solution of 2 g of the product of Preparation 1 dissolved in 20 ml of tetrahydrofuran, cooled to -70 ° C is added in 30 minutes 15 ml of a 1.6 N solution of n- butyllithium in hexane. After 30 minutes of contact, 2.17 ml of bromocyclohexane are cast in 25 minutes and the reaction medium is gradually reduced to -20 ° C and then poured into a saturated solution of ammonium chloride and finally extracted with ether. Purification on silica (dichloromethane / ethyl acetate 95/5) gives the expected product in the form of an oil.

    Stade 2 : 6-Cyano-6-cyclohéxyl-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamideStep 2 : 6-Cyano-6-cyclohexyl-N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide

    0,33 g du produit obtenu au stade 1 sont traités par 0,25 g du composé de la préparation 8, selon le procédé décrit à l'exemple 1, permettant d'obtenir le produit attendu.
    Point de fusion : 224-227°C     0.33 g of the product obtained in Stage 1 are treated with 0.25 g of the compound of Preparation 8, according to the process described in Example 1, to obtain the expected product.
    Melting point : 224-227 ° C

    EXEMPLE 11 : 6-Cyclohéxyl-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 11: 6-cyclohexyl N - (3-pyridinyl) -2,3,5,6-tetrahydro-1 H -cyclobuta [f] indole-1-carboxamide Stade 1 : 6-Cyclohéxyl-2,3,5,6-tétrahydro-1H-cyclobuta[f]indoleStep 1 : 6-Cyclohexyl-2,3,5,6-tetrahydro-1H-cyclobuta [f] indole

    Une solution de 0,5 g de produit obtenu au stade 1 de l'exemple 10 dans 10 ml de tétrahydrofurane anhydre et 0,11 ml d'éthanol absolu sont coulés sur 20 ml d'ammoniac liquide à une température de -78°C, puis 0,15 g de sodium sont introduits par portions. Après 30 minutes de contact à cette température le milieu réactionnel est traité par 0,83 g de chlorure d'ammonium. Après évaporation de l'ammoniac, le résidu est repris par une solution saturée de chlorure d'ammonium, extrait à l'éther et les phases éthérées sont lavées, séchées et concentrées pour conduire au produit attendu.A solution of 0.5 g of product obtained in Step 1 of Example 10 in 10 ml of anhydrous tetrahydrofuran and 0.11 ml of absolute ethanol are poured onto 20 ml of ammonia liquid at a temperature of -78 ° C, then 0.15 g of sodium are introduced in portions. After 30 minutes of contact at this temperature, the reaction medium is treated with 0.83 g of ammonium chloride. After evaporation of the ammonia, the residue is taken up by a saturated solution of ammonium chloride, extracted with ether and the ethereal phases are washed, dried and concentrated to yield the expected product.

    Stade 2 : 6-Cyclohéxyl-N-(3-pyridinyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide Step 2 : 6-Cyclohexyl-N- (3-pyridinyl) -2,3,5,6-tetrahydro-1H-cyclobuta [f] indole-1-carboxamide

    0,43 g du produit obtenu au stade 1 sont traités par 0,36 g du composé de la préparation 8, selon le procédé décrit à l'exemple 1, permettant d'obtenir le produit attendu.
    Point de fusion : 187-190°C (M.K.)     0.43 g of the product obtained in Stage 1 are treated with 0.36 g of the compound of Preparation 8, according to the process described in Example 1, to obtain the expected product.
    Melting point: 187-190 ° C (MK)

    EXEMPLE 12 : 6-Cyano-N-{6-[(2-méthyl-3-pyridinyl)oxy]-3-pyridinyl}-6-(phénylsulfanyl)-2,3,5,6-tétrahydro-1H-cyclobuta[f]indole-1-carboxamide EXAMPLE 12 6-Cyano- N - {6 - [(2-methyl-3-pyridinyl) oxy] -3-pyridinyl} -6- (phenylsulfanyl) -2,3,5,6-tetrahydro- 1H- cyclobuta [ f ] indole-1-carboxamide

    Un mélange composé de 0,5 g du produit obtenu u stade 1 de l'exemple 9, 0,6 g du produit de la préparation 9, 0,16 ml de triéthylamine et 16 ml de diméthylformamide est porté à 100°C pendant 1 heure. Après évaporation de la diméthylformamide, le résidu est repris par 100 ml de dichlorométhane, lavé avec de la soude à 10%, à l'eau, puis séché et concentré sous pression réduite, pour conduire après purification sur silice (dichlorométhane/ éthanol/NH4OH / 98/2/0,4) et recristallisation de l'acétonitrile, au produit attenduA mixture consisting of 0.5 g of the product obtained in Stage 1 of Example 9, 0.6 g of the product of Preparation 9, 0.16 ml of triethylamine and 16 ml of dimethylformamide is heated at 100 ° C. for 1 hour. hour. After evaporation of the dimethylformamide, the residue is taken up in 100 ml of dichloromethane, washed with 10% sodium hydroxide, with water, then dried and concentrated under reduced pressure, to conduct after purification on silica (dichloromethane / ethanol / NH 4 OH / 98/2 / 0.4) and recrystallization of acetonitrile, to the expected product

    ETUDE PHARMACOLOGIQUE DES COMPOSES DE L'INVENTIONPHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXEMPLE 13 : Test de conflit de Vogel EXAMPLE 13 : Vogel Conflict Test

    Le test s'effectue sur des rats mâles Wistar (IFFA-CREDO) de poids 230-250 g, stabulés en animalerie par groupes de 4 sur sciure, dans des cages avec boisson et nourriture à volonté pendant 5 jours avant leur utilisation et soumis aux conditions suivantes : température (21 ± 1°C), humidité (60 ± 5 %) et cycle diurne de 12 heures (7:00 à 19:00 h). Le lundi suivant leur arrivée, les animaux sont transférés dans la pièce d'expérimentation où ils séjourneront jusqu'au vendredi, jour de Test. Pendant 4 jours, du lundi au jeudi inclus, les animaux n'ont alors qu'une seule heure par jour d'accès à la boisson (de 9:00 à 10:00 h).
    La veille du test, à partir de 15:00 h, les animaux sont isolés dans des cages sur grille, sans boisson ni nourriture.
    Le test se déroule dans une cage plastique transparente située dans une enceinte insonorisée et ventilée. La cage comporte un plancher en acier chromé. L'embout métallique du flacon contenant la boisson pénètre dans la cage à une hauteur de 6 cm au-dessus du plancher métallique. Le plancher et l'embout du flacon sont reliés par des câbles électriques à un appareil qui assure l'enregistrement des lèchements de l'animal et contrôle l'administration des chocs électriques. L'appareil est réglé de telle sorte que l'animal reçoit un choc électrique (entre embout et plancher métallique) tous les 20 lèchements de l'embout.
    Le jour du test, l'animal reçoit une injection (s.c.) de sérum physiologique (Témoin) ou de produit à tester, 30 minutes avant d'être placé dans la cage Test. La session débute dès que l'animal a effectué 20 lèchement et a reçu un premier choc électrique (durée 0,5 sec, intensité 0,300 mA). Pendant 3 minutes, l'animal reçoit un choc électrique chaque fois qu'il effectue 20 lèchements.
    Les résultats sont les nombres de lèchements et de chocs reçus par l'animal pendant les 3 minutes du Test.
    Les nombres de lèchements et de chocs reçus par les animaux traités sont comparés à ceux respectifs des animaux témoins, par analyse de variance, suivie d'un test de Dunnett avec P < 0,05. Un produit anxiolytique augmente le nombre de lèchements et de chocs reçus par l'animal, par rapport aux Témoins. A titre indicatif, le nombre moyen de lèchements non punis chez des animaux assoiffés est de 674,9 ± 44,5 (N = 7) en 3 minutes.
    L'efficacité d'un produit est exprimée par la dose minimale efficace (M.E.D.), c'est-à-dire la plus faible dose produisant une différence significative par rapport aux Témoins. Cette dose est de 2,5 mg/kg, s.c. pour le produit de l'exemple 1. Résultats du produit de l'exemple n°1 Doses mg/kg, s.c. Lèchements punis (1 choc/20 lèchements) N 0 142,7 ± 31,9 10 0,63 197,5 ± 59,5 8 2,5 560,1 ± 67,0 8 10,0 499,3 ± 95,3 7     The test is carried out on Wistar male rats (IFFA-CREDO) weighing 230-250 g, housed in pet shops in groups of 4 on sawdust, in cages with drink and food at will for 5 days before their use and submitted to the following conditions: temperature (21 ± 1 ° C), humidity (60 ± 5%) and daytime cycle of 12 hours (7:00 to 19:00 h). On the Monday following their arrival, the animals are transferred to the experimental room where they will stay until Friday, the day of Test. For 4 days, from Monday to Thursday, the animals have only one hour per day of access to the drink (from 9:00 to 10:00).
    The day before the test, from 15:00 pm, the animals are isolated in grid cages, without drink or food.
    The test takes place in a transparent plastic cage located in a soundproof and ventilated enclosure. The cage has a chromed steel floor. The metal tip of the bottle containing the drink enters the cage at a height of 6 cm above the metal floor. The floor and the tip of the bottle are connected by electrical cables to a device that records the licking of the animal and controls the administration of electric shocks. The apparatus is set so that the animal receives an electric shock (between tip and metal floor) every 20 lobes of the tip.
    On the day of the test, the animal receives an injection (sc) of physiological saline (control) or product to be tested, 30 minutes before being placed in the test cage. The session begins as soon as the animal has licked 20 and received a first electric shock (duration 0.5 sec, intensity 0.300 mA). For 3 minutes, the animal receives an electric shock each time it performs 20 licks.
    The results are the numbers of licks and shocks received by the animal during the 3 minutes of the test.
    The numbers of licks and shocks received by the treated animals are compared with those of the control animals, by analysis of variance, followed by a Dunnett test with P <0.05. An anxiolytic product increases the number of licks and shocks received by the animal, compared to the controls. As an indication, the average number of non-punished licks in thirsty animals is 674.9 ± 44.5 (N = 7) in 3 minutes.
    The effectiveness of a product is expressed by the minimum effective dose (MED), ie the lowest dose producing a significant difference compared to controls. This dose is 2.5 mg / kg, sc for the product of Example 1. Product results from Example 1 Doses mg / kg, sc Licks punished (1 shock / 20 licks) NOT 0 142.7 ± 31.9 10 0.63 197.5 ± 59.5 8 2.5 560.1 ± 67.0 8 10.0 499.3 ± 95.3 7

    EXEMPLE 14 : Test d'enfouissement des billes chez la souris EXAMPLE 14 : Burrow burrowing test in mice

    Ce test permet d'évaluer la capacité d'agents pharmacologiques à inhiber le comportement spontané d'enfouissement de billes chez la souris, cette inhibition étant prédictive d'actions antidépressive et/ou anti-impulsive. Des souris mâles de souche NMRI (Iffa-Credo, L'Arbresle, France), pesant 20-25 g le jour de l'expérience, sont placées individuellement dans des boítes en Macrolon (30 x 18 x 19 cm) contenant 5 cm de sciure et recouvertes par une plaque en plexiglass perforée. Vingt-quatre billes en verre "oeil de chat" sont réparties régulièrement sur la sciure à la périphérie de la boíte. Au terme de 30 minutes d'exploration libre, les animaux sont retirés de la boíte et le nombre de billes enfouies est comptabilisé.
    A titre d'exemple, la MED (dose minimale efficace) pour le produit de l'exemple 1 est de 2,5 mg/kg s.c.    This test makes it possible to evaluate the ability of pharmacological agents to inhibit spontaneous burrowing behavior in mice, this inhibition being predictive of antidepressant and / or anti-impulsive actions. Male mice of NMRI strain (Iffa-Credo, L'Arbresle, France), weighing 20-25 g on the day of the experiment, are placed individually in Macrolon boxes (30 x 18 x 19 cm) containing 5 cm of sawdust and covered by a perforated plexiglass plate. Twenty-four glass balls "cat's eye" are regularly distributed on the sawdust on the periphery of the box. After 30 minutes of free exploration, the animals are removed from the box and the number of buried logs is counted.
    By way of example, the MED (minimum effective dose) for the product of Example 1 is 2.5 mg / kg sc

    EXEMPLE 15 : Composition pharmaceutique : comprimés EXAMPLE 15 : Pharmaceutical composition: tablets

    Formule de préparation pour 1000 comprimés dosés à 5 mgPreparation formula for 1000 tablets dosed at 5 mg Composé de l'exemple 1Composed of Example 1 5 g5 g Hydroxypropylméthylcellulosehydroxypropyl methylcellulose 5 g5 g Amidon de bléWheat starch 10 g10 g LactoseLactose 100 g100 g Stéarate de MagnésiumMagnesium Stearate 2 g2 g

    Claims (11)

    1. Compounds of formula (I) :
      Figure 00590001
      wherein :
      n represents an integer of from 0 to 6,
      R1 represents a group selected from hydrogen, hydroxy, cyano, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkoxycarbonyl, carboxy, aminocarbonyl (the amino moiety optionally being substituted by one or two identical or different groups selected from linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched) and NR4R5 wherein R4 and R5, which may be identical or different, represent a group selected from linear or branched (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, heteroaryl, heteroaryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, cycloalkyl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, linear or branched (C2-C6)alkenyl and linear or branched (C2-C6)alkynyl,
      R2 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, hydroxymethyl, a group of formula
      Figure 00590002
      and -U-V-W
      wherein :
      T represents a monocyclic or polycyclic (C3-C12)cycloalkyl group, it being possible for one of the carbon atoms of the cycloalkyl optionally to be replaced by a group selected from oxygen, selenium, a group of formula S(O)p wherein p represents an integer of from 0 to 2 inclusive, and a group of formula SiR6R7 wherein R6 and R7, which may be identical or different, represent a linear or branched (C1-C6)alkyl group,
      U represents a bond or a methylene group,
      V represents a bond, an oxygen atom or a group S(O)q wherein q is an integer of from 0 to 2 inclusive, and
      W represents a group selected from aryl, aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, cycloalkyl, and cycloalkyl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched,
      and
      R3 represents a group selected from hydrogen, linear or branched (C1-C6)alkyl, aryl and heteroaryl,
      their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base,
      wherein:
      an aryl group is to be understood as a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl, each of which groups is optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, nitro, cyano, linear or branched (C1-C6)trihaloalkyl, amino, monoalkylamino, di-(C1-C6)alkylamino in which the alkyl moieties may be linear or branched, (C1-C6)trihaloalkoxy in which the alkoxy moiety may be linear or branched, amino-(C1-C6)alkylaminocarbonyl (the nitrogen atoms of each of the amino moieties optionally being substituted by identical or different linear or branched (C1-C6)alkyl groups), pyridyl, pyridyloxy and pyridyloxymethyl, the latter three groups optionally being substituted by a linear or branched (C1-C6)alkyl group,
      a heteroaryl group is to be understood as an aromatic monocyclic system, or a bicyclic system in which one of the rings is aromatic and the other ring is aromatic or partially hydrogenated, having from 5 to 12 ring members and containing one, two or three identical or different hetero atoms selected from oxygen, nitrogen and sulphur, each of the groups optionally being substituted by one or more identical or different groups selected from the substituents described for the aryl group defined above,
      and a cycloalkyl group is to be understood as a mono- or poly-cyclic system having from 3 to 12 ring members and optionally containing one or more unsaturated bonds,
      wherein the unsaturated bonds do not confer an aromatic character on the said ring system.
    2. Compounds of formula (I) according to claim 1, characterised in that R2 represents a hydrogen atom, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    3. Compounds of formula (I) according to claim 1, characterised in that R2 represents a group of formula
      Figure 00610001
      wherein T is as defined for formula (I), n is 1, and
      R1 represents a cyano group or an amino group substituted by one or two identical or different groups selected from linear or branched (C1-C6)alkyl and aryl-(C1-C6)alkyl in which the alkyl moiety may be linear or branched, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    4. Compounds of formula (I) according to claim 1, characterised in that n is 0, R1 represents a hydrogen atom or a cyano group and R2 represents a hydrogen atom, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    5. Compounds of formula (I) according to claim 1, characterised in that n is 0, R1 represents a hydrogen atom or a cyano group and R2 represents a group of formula -U-V-W wherein U represents a single bond, V represents a group of formula S(O)p wherein p is as defined for formula (I) and W represents an aryl group, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    6. Compounds of formula (I) according to claim 1, characterised in that R3 represents a heteroaryl group, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    7. Compounds of formula (I) according to claim 1, characterised in that R3 represents a pyridyl group, their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    8. Compounds of formula (I) according to claim 1 that are :
      N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      5-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      6-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      6-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      5-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      7-cyano-N-(3-pyridyl)-1,2,6,7-tetrahydro-3H-cyclobuta[e]indole-3-carboxamide,
      7-(hydroxymethyl)-N-(3-pyridyl)-2,3,6,7-tetrahydro-1H-cyclobuta[g]indole-1-carboxamide,
      6-[(dimethylamino)methyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      6-cyano-6-(phenylsulphanyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      6-cyano-6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      6-cyano-N-{6-[(2-methyl-3-pyridyl)oxy]-3-pyridyl}-6-(phenylsulphanyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,
      their isomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
    9. Process for the preparation of the compounds of formula (I), characterised in that there is used as starting material a compound of formula (II) :
      Figure 00630001
      wherein R'1 represents a group selected from hydrogen, cyano, hydroxymethylene, carboxy and linear or branched (C1-C6)alkoxycarbonyl,
      which compound of formula (II) is reacted, under the conditions of reductive amination, with a compound of formula (III) : (AO)2CHCHO   (III) wherein A represents a linear or branched (C1-C6)alkyl group, to yield the compounds of formula (IV) :
      Figure 00630002
      wherein A and R'1 are as defined hereinbefore,
      which compounds of formula (IV) are treated with a compound of formula (V) : ClSO2E   (V) wherein E represents a linear or branched (C1-C4)alkyl group, phenyl or p-toluyl, to yield the compounds of formula (VI) :
      Figure 00630003
      wherein A, E and R'1 are as defined hereinbefore,
      which compounds of formula (VI) are cyclised under acid conditions to yield the compounds of formula (VII) :
      Figure 00640001
      wherein E and R'1 are as defined hereinbefore,
      which compounds of formula (VII) are treated either with an alkali metal hydroxide in an alcoholic solvent or with sodium in liquid ammonia to yield the compounds of formula (VIII) :
      Figure 00640002
      wherein R', is as defined hereinbefore,
      which compounds of formula (VIII) are then reduced, in accordance with the conventional conditions of organic synthesis, to yield the compounds of formula (IX) :
      Figure 00640003
      wherein R'1 is as defined hereinbefore,
      which compounds of formula (IX) are treated with an isocyanate of formula (X) : R3 - N = C = O   (X) wherein R3 is as defined for formula (I),
      to yield the compounds of formula (I/a), a particular case of the compounds of formula (I):
      Figure 00640004
      wherein R'1 and R3 are as defined hereinbefore,
      or which compounds of formula (IX), in the case where R'1 represents a cyano group, are treated :
      * either with a ketone of formula (XI) :
      Figure 00650001
      wherein T is as defined for formula (I), to yield the compounds of formula (XII) :
      Figure 00650002
      wherein T is as defined hereinbefore,
      which compounds of formula (XII) are then :
         
      Figure 00650003
      either treated with an isocyanate of formula (X) as described hereinbefore to yield the compounds of formula (I/b), a particular case of the compounds of formula (I),
      Figure 00650004
      wherein T and R3 are as defined hereinbefore,
          or , after protection of the amine of the indoline group, reduced according to the conventional methods of organic synthesis to yield the compounds of formula (XIII) :
      Figure 00650005
      wherein T is as defined hereinbefore and P1 is a conventional protecting group,
      the primary amine function of which compounds of formula (XIII) is then substituted and converted to a secondary and then tertiary amine function, using conventional methods of organic chemistry, to yield the compounds of formula (XIV) :
      Figure 00660001
      wherein R4 and R5 are as defined for formula (I) and T and P1 are as defined hereinbefore,
      which compounds of formula (XIV), after deprotection of the nitrogen atom of the indoline nucleus, are treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/c), a particular case of the compounds of formula (I) :
      Figure 00660002
      wherein T, R4, R5 and R3 are as defined hereinbefore,
      * or with a strong base or an alkali metal alcoholate, in the presence of a compound of formula (XV) : W1 - X   (XV) wherein W1 represents a linear or branched (C1-C6)alkyl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, a cycloalkyl group, or a cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety may be linear or branched, and X represents a leaving group, such as a halogen atom or a trifluoromethylsulphonate, mesylate or tosylate group,
      to yield the compounds of formula (XVI) :
      Figure 00670001
      wherein W1 is as defined hereinbefore,
      which compounds of formula (XVI) are :
          either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/d), a particular case of the compounds of formula (I) :
      Figure 00670002
      wherein W1 and R3 are as defined hereinbefore,
          or, after protection of the nitrogen atom of the indoline nucleus, converted like the compounds of formula (XII) to a primary, secondary and then tertiary amine to yield, after deprotection and treatment in the presence of a compound of formula (X) as described hereinbefore, the compounds of formula (I/e), a particular case of the compounds of formula (I) :
      Figure 00670003
      wherein W1, R3, R4 and R5 are as defined hereinbefore,
      * or with bromine in a chlorine-containing organic solvent to yield the compounds of formula (XVII) :
      Figure 00680001
      which compounds of formula (XVII) are reacted with a compound of formula (XVIII) : W - V1 - H   (XVIII) wherein W is as defined for formula (I) and V1 represents an oxygen atom or a sulphur atom,
      to yield the compounds of formula (XIX) :
      Figure 00680002
      wherein V1 and W are as defined hereinbefore,
      which compounds of formula (XIX) are :
          either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/f), a particular case of the compounds of formula (I) :
      Figure 00680003
      wherein R3, V, and W are as defined hereinbefore,
      which compounds of formula (I/f), in the case where V1 represents a sulphur atom, may be subjected to oxidation under conventional conditions of organic synthesis to yield the compounds of formula (I/g), a particular case of the compounds of formula (I) :
      Figure 00690001
      wherein R3 and W are as defined for formula (I) and q1 is an integer of from 1 to 2 inclusive,
          or protected and then converted, by the same sequence of reactions as the compounds of formula (XII), to a primary, secondary and tertiary amine to yield, after deprotection and treatment with a compound of formula (X), as described hereinbefore, the compounds of formula (I/h), a particular case of the compounds of formula (I):
      Figure 00690002
      wherein V1, W, R3, R4 and R5 are as defined hereinbefore,
      which compounds of formula (I/h), in the case where V, represents a sulphur atom, may be subjected to oxidation under conventional conditions of organic synthesis to yield the compounds of formula (I/i), a particular case of the compounds of formula (I) :
      Figure 00690003
      wherein W, R3, R4, R5 and q1 are as defined hereinbefore,
      * or with an alkali metal hydride in dimethylformamide, in the presence of formaldehyde, to yield the compounds of formula (XX) :
      Figure 00700001
      which compounds of formula (XX) are :
          either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/j), a particular case of the compounds of formula (I) :
      Figure 00700002
      wherein R3 is as defined for formula (I),
          or protected at the nitrogen atom of the indoline nucleus, then treated according to Mitsunobu reaction conditions with a compound of formula (XXI) : W - OH   (XXI) wherein W is as defined for formula (I),
      to yield, after deprotection of the nitrogen atom of the indoline nucleus, the compounds of formula (XXII) :
      Figure 00700003
      wherein W is as defined hereinbefore,
      which compounds of formula (XXII) are :
         ◆ either treated with a compound of formula (X) as described hereinbefore to yield the compounds of formula (I/k), a particular case of the compounds of formula (I) :
      Figure 00710001
      wherein R3 and W are as defined hereinbefore,
         ◆ or protected and then converted, by the same reaction sequence as the compounds of formula (XII), to a primary, secondary and tertiary amine to yield, after deprotection and treatment with a compound of formula (X), as described hereinbefore, the compounds of formula (I/l), a particular case of the compounds of formula (I) :
      Figure 00710002
      wherein R3, R4, R5 and W are as defined hereinbefore,
      the compounds (I/a) to (I/l) constituting the totality of the compounds of the invention, which compounds are purified, if necessary, according to a conventional purification technique, may be separated, if desired, into their different isomers according to a conventional separation technique, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base.
    10. Pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) according to any one of claims I to 9, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
    11. Pharmaceutical compositions according to claim 10 containing at least one active ingredient according to any one of claims 1 to 9 for use as medicaments in the treatment of anxiety, panic attacks, obsessive-compulsive disorders, phobias, impulsive disorders, drug abuse, cognitive disorders, psychoses, depression and mood disorders.
    EP01400939A 2000-04-13 2001-04-12 CNS active cyclobuta-indole carboxamide derivatives, processes for their preparation and pharmaceutical compositions containing them Expired - Lifetime EP1146044B1 (en)

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    JPH09512025A (en) * 1994-04-23 1997-12-02 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー Tricyclic derivatives as 5HT-lower 2C and 5HT-lower 2B antagonists
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    ES2267253T3 (en) * 1998-02-27 2007-03-01 The Board Of Trustees Of The University Of Illinois AGENTS WITH ACTIVITY RELATED TO SEROTONINE FOR THE TREATMENT OF THE SLEEP APNEA.

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    EA200100344A2 (en) 2001-10-22
    ZA200103064B (en) 2001-10-18
    US20030032812A1 (en) 2003-02-13
    US20010044426A1 (en) 2001-11-22
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    PL347046A1 (en) 2001-10-22
    DE60105219D1 (en) 2004-10-07
    TR200402685T4 (en) 2004-11-22
    NO318206B1 (en) 2005-02-14
    PT1146044E (en) 2004-11-30
    EP1146044A1 (en) 2001-10-17
    DK1146044T3 (en) 2004-12-27
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    US6743818B2 (en) 2004-06-01
    EA200100344A3 (en) 2002-02-28
    KR20010098581A (en) 2001-11-08
    CN1323796A (en) 2001-11-28
    HK1040247A1 (en) 2002-05-31
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